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EUnetHTA WP5 Joint Action 2 (2012-2015) Strand B, Rapid assessment of other health technologies such as medical devices, surgical interventions or diagnostics RENAL DENERVATION SYSTEMS FOR TREATMENT-RESISTANT HYPERTENSION Pilot rapid assessment of other health technologies using the HTA Core Model for Rapid Relative Effectiveness Assessment Assessment Pilot ID: WP5-SB-12 Version 1.3, 18 December 2013 Final version

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EUnetHTA JA2 Renal denervation systems or treatment-resistant hypertension WP5B

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EUnetHTA WP5 Joint Action 2 (2012-2015) Strand B, Rapid assessment of

other health technologies such as medical devices, surgical interventions or

diagnostics

RENAL DENERVATION SYSTEMS FOR TREATMENT-RESISTANT HYPERTENSION

Pilot rapid assessment of other health technologies using the HTA Core Model

for Rapid Relative Effectiveness Assessment

Assessment

Pilot ID: WP5-SB-12

Version 1.3, 18 December 2013

Final version

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DOCUMENT HISTORY

Version Date Description

V1.0 04 10 2013 First draft

V1.1 28 10 2013

With input from dedicated reviewers

(review period: 7-21October 2013)

V1.2 04 12 2013

With input from manufacturers, Strand B members,

patient representative and external clinical experts

(review period: 28 October – 18 November 2013)

V1.3 18 12 2013 Final version with input from medical editing

(review period: 4-11 December 2013)

This assessment was produced by experts from the institutions below and was reviewed

by members of Work Package 5 (WP5) Joint Action 2 of the EUnetHTA network; the entire

process was coordinated by the Ludwig Boltzmann Institute for Health Technology Assess-

ment (LBI-HTA).

Disclaimer: This assessment represents a consolidated view of the non-binding recom-

mendations of the EUnetHTA network members and is in no case the official opinion of

the participating institutions or individuals. EUnetHTA Joint Action 2 is supported by a

grant from the European Commission. The sole responsibility for the content of this

document lies with the authors and neither the European Commission nor EUnetHTA are

responsible for any use that may be made of the information contained therein.

Authors Norwegian Knowledge Centre for the

Health Services (NOKC), Norway

Katrine B. Frønsdal

Tove Ringerike

Co-Authors

Galician Health Technology Assessment

Agency (Avalia-t), Spain

Leonor Varela Lema

Gerardo Atienza Merino

Public Health and Quality Improvement,

Central Denmark Region (CFK), Denmark

Karla Douw

Claus Løvschall

Reviewers

Healthcare Improvement Scotland (HIS),

United Kingdom

Karen MacPherson

Susan Myles

Hilda Emengo

Finnish Office for Health Technology

Assessment/National Institute for

Health and Welfare (FinOHTA/THL), Finland

Neill Booth

Sinikka Sihvo

Agency for Health Technology Assessment

in Poland (AHTAPol), Poland

Michal Antoni Witkowski

Urszula Cegłowska

Anna Zawada

The National Institute for Quality and

Organisational Development in Health Care

and Medicine (GYEMSZI), Hungary

Zoltan Huszti

Institute for Quality and Efficiency in

Health Care (IQWiG), Germany Stefan Sauerland

External

Reviewers

Haukeland University Hospital, Bergen,

Norway Jan Erik Nordrehaug

University of Bologna, Italy Giuseppe Boriani

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Contact information

Authors:

Katrine B. Frønsdal, Norwegian Knowledge Centre for the Health Services, Boks 7004,

St. Olavs plass, N-0130 Oslo, Norway

Phone: +47 99254920

E-mail: [email protected]

Tove Ringerike, Norwegian Knowledge Centre for the Health Services, Boks 7004,

St. Olavs plass, N-0130 Oslo, Norway

Phone: +47 23255000

E-mail: [email protected]

Co-Authors:

Leonor Varela Lema, Galician Health Technology Assessment Agency,

Galician Department of Health, Edificio Administrativo San Lázaro s/n,

15781 Santiago de Compostela, Spain

Phone: + 34 881548609

E-mail: [email protected]

Gerardo Atienza Merino, Galician Health Technology Assessment Agency,

Galician Department of Health, Edificio Administrativo San Lázaro s/n,

15781 Santiago de Compostela, Spain

Phone: + 34 881548609

E-mail: [email protected]

Karla Douw, Public Health and Quality Improvement, Central Denmark Region,

Olof Palmes Allé 15, DK-8200 Aarhus N, Denmark

Phone: +45 78414372

E-mail: [email protected]

Claus Løvschall, Public Health and Quality Improvement, Central Denmark Region,

Olof Palmes Allé 15, DK-8200 Aarhus N, Denmark

Phone: +45 78414354

E-mail: [email protected]

Comments on Version 1.1 of the pilot rapid assessment were received

from the following WP5 Strand B members:

Strand B

members

Healthcare Improvement Scotland (HIS), Scotland Hilda Emengo

Regione Veneto, Italy Teresa Gasparetto

USCS A. Gemelli University Hospital, Italy Carmen Furno

National Institute for Health and Welfare (THL),

Finland

Neill Booth

Health Information and Quality Authority (HIQA),

Ireland

Patricia Harrington

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Stakeholder involvement

1) Project Plan

SAG:

Comments received from:

Eucomed Covidien St. Jude Medical Association Internationale de la Mutualité (AIM) Johnson & Johnson

Answered but no comments:

Caisse Nationale d'assurance Maladie (CNAMTS) Siemens AG Standing Committee of European Doctors (CPME)

Public Consultation:

Comments received from:

Johnson & Johnson European Organisation for rare diseases (EURORDIS) Beaumont Hospital St. George’s NHS Trust University of Milano-Bicocca University of Valencia University of Barcelona Hauptverband der österreichischen Sozialversicherungsträger (HVB)

Manufacturers:

Comments received from:

Medtronic Vascular Boston Scientific Covidien St. Jude Medical

2) Pilot Rapid Assessment

Patient representative(s):

European Organisation for Rare Diseases (EURORDIS)

Manufacturer(s):

Medtronic Vascular Boston Scientific Covidien St. Jude Medical Johnson & Johnson Medical BV/Biosense Webster ReCor Medical Eucomed Hypertension Working Group

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Conflict of interest:

One external reviewer declared a conflict of interest, but as it was deemed irrelevant per

the Procedure Manual for WP5 Strand B, the respective reviewer was not excluded from

the pilot process. All authors and other reviewers who were involved in the production of

this pilot assessment have declared that they have no conflicts of interest in relation to

the technology that has been assessed, per the EUnetHTA conflicts of interest (COI)

statement form.

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TABLE OF CONTENTS

SUMMARY OF RELATIVE CLINICAL EFFECTIVENESS OF

RENAL DENERVATION SYSTEMS ........................................................................................................ 7

SCOPE ...................................................................................................................................................... 7 INTRODUCTION ........................................................................................................................................ 8 METHODS ................................................................................................................................................ 9 RESULTS ................................................................................................................................................ 10 DISCUSSION ........................................................................................................................................... 13 CONCLUSION ......................................................................................................................................... 14

LIST OF ABBREVIATIONS ..................................................................................................................... 15

1 SCOPE ................................................................................................................................................. 17

2 HEALTH PROBLEM AND CURRENT USE OF THE TECHNOLOGY ................................... 19

2.1 METHODS .............................................................................................................................................. 19 2.2 MAIN RESULTS ...................................................................................................................................... 20 2.3 DISCUSSION ........................................................................................................................................... 23

3 DESCRIPTION AND TECHNICAL CHARACTERISTICS OF THE TECHNOLOGY .......... 24

3.1 METHODS .............................................................................................................................................. 24 3.2 MAIN RESULTS ...................................................................................................................................... 25 3.3 DISCUSSION ........................................................................................................................................... 29

4 SAFETY .............................................................................................................................................. 31

4.1 METHODS .............................................................................................................................................. 31 4.2 MAIN RESULTS ...................................................................................................................................... 32 4.3 DISCUSSION ........................................................................................................................................... 37

5 CLINICAL EFFECTIVENESS ........................................................................................................ 39

5.1 METHODS .............................................................................................................................................. 39 5.2 MAIN RESULTS ...................................................................................................................................... 41 5.3 DISCUSSION ........................................................................................................................................... 43

6 REFERENCES ................................................................................................................................... 45

APPENDIX 1: METHODS AND DESCRIPTION OF THE EVIDENCE USED ................................. 51

METHODS .............................................................................................................................................. 51 DESCRIPTION OF THE EVIDENCE USED ................................................................................................... 57

APPENDIX 2: RESULT CARDS .............................................................................................................. 86

HEALTH PROBLEM AND CURRENT USE OF THE TECHNOLOGY .............................................................. 86 DESCRIPTION AND TECHNICAL CHARACTERISTICS OF TECHNOLOGY .................................................. 102 SAFETY ............................................................................................................................................... 117 CLINICAL EFFECTIVENESS ................................................................................................................... 131

APPENDIX 3: CHECKLIST FOR POTENTIAL ETHICAL, ORGANISATIONAL,

SOCIAL AND LEGAL ASPECTS ................................................................................ 150

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SUMMARY OF RELATIVE CLINICAL EFFECTIVENESS OF RENAL

DENERVATION SYSTEMS

The assessment element ID codes in brackets (e.g. A0001) refer to the result cards

in Appendix 1, which give details on the relevant results.

Scope

Population Patients with treatment-resistant arterial hypertension (defined as persistent

hypertension despite administration of at least 3 antihypertensive drugs in

adequate doses, including a diuretic) with blood pressure ≥ 140/90 mm Hg

(Calhoun 2008; Mancia 2013) and without secondary cause of hypertension.

Intervention Renal nerve ablation and denervation systems

This intervention entails the destruction of efferent sympathetic nerves and

afferent nerves in the wall of the renal arteries to reduce sympathetic nerve

traffic, thereby reducing blood pressure.

Comparator(s) Standard of care (which includes here: no treatment, additional pharmacological

treatment, device-based therapy for hypertension and sham treatment)

All patients continue treatment with at least 3 hypertensive drugs. Any

additional intervention or comparator is administered as add-on therapy.

Outcome(s) Primary outcomes:

Overall mortality

Cardiovascular mortality

Cardiovascular morbidity (stroke, myocardial infarction, heart failure)

Blood pressure (changes in systolic and diastolic blood pressure)

Complications during or after treatment

Secondary outcomes:

Left ventricular hypertrophy/systolic and diastolic cardiac function

Kidney function

Quality of life

Effect on daily living

Study design Efficacy/effectiveness: Systematic reviews (SRs)/Health Technology

Assessments (HTAs), randomised controlled trials (RCTs) and, if data from

RCTs are lacking or insufficient, prospective, controlled studies

Safety: Same as for efficacy and including all prospective studies

Languages English, Spanish, French, German, Swedish, Danish, Norwegian

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Introduction

Health problem

The target population comprises patients who suffer from resistant hypertension, a con-

dition that is linked to sympathetic nervous system overactivity, involving the kidneys.

Patients who are eligible for the intervention can be treated with catheter-based renal

denervation. The goals of the treatment are to prevent hypertensive end-organ damage

and decrease cardiovascular morbidity and mortality (A0007).

Treatment-resistant hypertension is a condition for which conventional/traditional treat-

ments are inadequate – this condition is also described as true resistant hypertension.

The traditional/standard treatment is based primarily on medical treatment and lifestyle

interventions. Resistant hypertension develops when the appropriate treatments, includ-

ing lifestyle measures and 3 antihypertensive drugs (1 of which is a diuretic), fail to low-

er systolic blood pressure (BP) and diastolic BP values to 140 and 90 mm Hg, respectively.

All drug agents should be prescribed at the optimal doses. Any secondary causes (due to

other diseases, primarily renal disease) must also be ruled out (A0002).

Risk factors for treatment-resistant arterial hypertension are older age, lifestyle factors

(e.g. obesity or large weight gains, excessive alcohol consumption, high sodium intake),

chronic intake of vasopressors or sodium-retaining substances, obstructive sleep apnoea,

undetected secondary forms of hypertension and advanced and irreversible organ dam-

age, particularly when it involves renal function or markedly increases the arteriolar wall–

lumen ratio or reduces large artery distensibility (A0003).

The natural course of resistant hypertension has been inadequately examined. If un-

treated, hypertension will increase the risk of cardiovascular disease, stroke and renal

failure. Patients frequently encounter associated cardiovascular risk factors, such as dia-

betes, obstructive sleep apnoea and left ventricular hypertrophy (A0004). Normally, the

patient does not experience symptoms that are associated with resistant hypertension.

Some patients might experience fatigue, headache or nosebleed – symptoms that are

related to higher BP (A0005).

Overall, the exact prevalence of resistant hypertension is unknown. It is, however, assumed

to be a common clinical condition. Based on the aforementioned risk factors, the preva-

lence is expected to increase in the older and more obese population. The prevalence of

resistant hypertension ranges from 5% to 30% of the overall hypertensive population but

is likely below 10%. The prevalence of all cases of hypertension is approximately 30% to

45% of the general population, also rising with older age (A0006).

In diagnosing resistant hypertension, one must first consider that most cases of resistant

hypertension originate from multiple factors and rarely have a single cause. Evaluation

should verify the diagnosis of hypertension – excluding pseudoresistant patients (e.g.

white-coat hypertension) – uncover any causes of secondary hypertension and clarify any

cardiovascular risk, organ damage and related clinical conditions. A medical history should

be included in the clinical evaluation, along with the family history with regard to hyper-

tension, a physical examination, laboratory investigations and further diagnostic tests.

The evaluation of patients with resistant hypertension should focus on confirming actual

treatment resistance (A0024).

As stated in an expert consensus document on catheter-based renal denervation that was

published in 2013 by the European Society of Cardiology, patients should comply with a

set of criteria before renal denervation is considered, as follows: i) office-based systolic

BP ≥ 160 mm Hg (≥150 mm Hg for those with type 2 diabetes) despite use of ≥ 3 antihy-

pertensive drugs at adequate dosages and combinations (including diuretics); ii) treatment

resistance to lifestyle modification when changes in lifestyle fails to alter the BP; iii) ex-

clusion of secondary hypertension; iv) exclusion of pseudo-resistance by monitoring am-

bulatory BP (average BP > 130 mm Hg or mean daytime BP > 135 mm Hg); v) preserved renal

function (glomerular filtration rate ≥ 45 ml/min/1.73 m2

) and vi) eligible renal arteries: no

polar or accessory arteries, no renal artery stenosis and no prior revascularization (B0002).

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The uncertain prevalence and potential number of candidates, based on the indications/

contraindications for the surgical procedure, render it difficult to calculate a reasonable

estimate on the expected annual utilisation of catheter-based renal denervation. Existing

data indicate many potential candidates for renal denervation. More experience with the

procedure in relevant candidates will clarify the relevant annual use of renal denervation

(A0011).

Description of technology

Renal denervation is a treatment for treatment-resistant hypertension that uses low-level

radio frequency energy or ultrasonography to disrupt renal sympathetic nerves to reduce

blood flow and thereby decrease hypertension by de-activating hyperactive nerves, with-

out affecting other abdominal, pelvic or lower-extremity nerves (B0001).

Most systems are catheter-based and introduce the catheter through the femoral artery,

which is threaded into the renal artery lumen (B0001) under fluoroscopic control. Renal

denervation should be performed in a catheterisation laboratory, for cardiovascular inter-

ventions and in a setting that specialises in hypertension treatment (B0004).

The current treatment regimen consists of a combination of at least 3 antihypertensive

agents. Renal denervation is intended to be add-on therapy to pharmaceutical treatment

(B0001, B0002).

Of the renal denervation systems that use radiofrequency energy, the Symplicity® (Med-

tronic, Ardian Inc.), OneShotTM

(Covidien), EnligHTNTM

(St. Jude Medical), Vessix V2TM

(Bos-

ton Scientific) and IberisTM

(Terumo) systems are CE-marked in Europe. Of the ultrasonog-

raphy devices that are under development, the PARADISETM

system (ReCor) has received

the CE mark. None of the systems is FDA-approved, but all .are seeking this status Med-

tronic’s Symplicity® system is the first system to be reviewed in the U.S. in a parallel review

program of the FDA and Centers for Medicare and Medicaid Services from 2014 (B0003).

Methods

‘Health problem’ and ‘Description of technology’ Domains

The ‘HTA Core Model for Rapid Relative Effectiveness Assessment for Pharmaceuticals’

was the only source that was used to select the relevant assessment elements. Overall, a

basic search (which was the same for all domains) was used as the springboard for an-

swering research questions. Additional searches were performed for nearly all research

questions using PubMed and Google. Google was also used for locating specific informa-

tion on each renal denervation (RDN) system.

‘Safety’ and ‘Clinical effectiveness’ Domains

The ‘HTA Core Model for Rapid Relative Effectiveness Assessment for Pharmaceuticals’

was the principal source that was used to select the relevant assessment elements. In

addition, assessment elements from ‘HTA Core Model for Medical and Surgical Interven-

tions 1.0r’ and ‘HTA Core Model for Diagnostic Technologies 1.0r’ were included for the

‘clinical effectiveness’ domain. Domain results were based on a basic systematic literature

search and on information from the manufacturers. The sources of information were

Embase (Ovid), Ovid MEDLINE, ISI Web of Knowledge, Cochrane Library, Cochrane Re-

views, Centre for Reviews and Dissemination and WHO ICTRP (International Clinical Trials

Registry Platform).

For ‘safety’, all prospective studies that were published in peer review journals were con-

sidered – i.e. randomised controlled trials (RCTs), non-randomised controlled trials (non-

RCTs) and case series. Conference abstracts and proceedings, editorials, opinion papers

and unpublished data were excluded. Data were extracted independently by 2 investiga-

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tors (discrepancies were resolved through discussion). Data were analysed qualitatively.

Quality was assessed using the Cochrane risk of bias checklist and GRADE, and informa-

tion was aggregated into evidence tables and displayed in plain text format.

For ‘clinical effectiveness’, the relevant literature was selected by 2 people independently,

as with ‘safety’, and discrepancies were discussed until a consensus was reached. In terms

of study design, systematic reviews (SRs)/Health Technology Assessments (HTAs), RCTs

and, if data from RCTs were lacking or insufficient, prospective, controlled studies were

selected to answer questions that were related to this domain. To assess the quality of

the SRs, the Norwegian Knowledge Centre for the Health Services (NOKC) checklist for

SRs, adapted from the Cochrane Effective Practice and Organisation of Care (EPOC) group

appraisal list for SRs, was used. The quality of the included individual studies was ana-

lysed using the Cochrane risk of bias checklist and GRADE. The quality of the evidence

was classified and defined as high (i.e. “We are very confident that the true effect lies close

to that of the estimate of the effect”), moderate (i.e. “We are moderately confident in the

effect estimate: the true effect is likely to be close to the estimate of the effect, but there

is a possibility that it is substantially different”), low (i.e. “Our confidence in the effect

estimate is limited: the true effect may be substantially different from the estimate of the

effect”) and very low (i.e. “We have very little confidence in the effect estimate: the true

effect is likely to be substantially different from the estimate of the effect”). Like for ‘safe-

ty’, the characteristics of the included SRs and single trials with quality assessments and

of ongoing studies that were identified from the trial registry searches are presented in

evidence tables and plain text format. When appropriate, meta-analyses were performed

using RevMan5.2. All data were reported per the PRISMA Statement.

Results

Available evidence

The evidence for the safety assessment came from 3 RCT publications, 3 non-RCT publi-

cations and 16 case series, comprising a total of 904 patients (however, 91 patients were

included in more than 1 study), with follow-up periods ranging from 3 months to 2 years.

In 2 of the 3 RCTs, all non-RCTs and 11 of the 16 cases series, the RDN procedure in-

volved the administration of radiofrequency ablation (RF) with the Symplicity® catheter

system (Medtronic) (784 patients in total.) One RCT of 13 patients performed the inter-

vention using the Navistar® ThermoCool® Irrigated Tip Catheter, designed for cardiac ab-

lation (Biosense Webster). One case study with 30 patients used the Marinr® RF ablation

catheter (also typically used for cardiac ablation), 1 with 46 patients used the EnligHTN®

multi-electrode renal denervation system and 1 with 9 patients used the OneShot™ (Co-

vidien) RDN system. Another case series included 11 patients who underwent RDN with

Paradise™ technology (ReCor Medical), which uses a catheter that emits ultrasonographic

energy, and 1 trial with 11 patients did not specify the type of system that was used (see

Appendix 1).

In the evaluation of clinical effectiveness, 3 SRs and 4 controlled studies – 3 RCTs and

1 non-RCT in a total of 158 patients with a follow-up period of 3 months to 1 year – were

included. In assessing changes in BP and based on the SR that was included, studies were

excluded if there was an overlap in patients with another study in the same analysis (in

which case the largest sample size of the 2 studies was selected). Thus, overlaps in pa-

tients were avoided; ultimately, 190 patients from 3 controlled trials were included for

this outcome.

In general, the SRs had slightly different inclusion criteria, but all searched for controlled

trials. Irrespective of how the individual studies were identified, all reviews included pa-

tients with resistant hypertension, and renal denervation was compared with no treat-

ment or sham procedure. Moreover, all patients continued with their usual pharmaceuti-

cal treatment for hypertension. Included SRs were rated as high-quality. Individual studies

were assessed using risk of bias and scored well with regard to bias within their study

type (see Appendix 1).

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Upcoming evidence

Searches in WHO ITRP (International Clinical Trials Registry Platform), performed in Octo-

ber 2013, identified 26 ongoing controlled studies that used various RDN systems, which

primarily examined changes in BP. None of the ongoing studies in this rapid assessment is

assessing overall mortality or cardiovascular mortality as the primary outcome. Feedback

from the manufacturers includes information that 1 study will evaluate the EnligHTNTM

Sys-

tem and its ability to reduce the risk of major cardiovascular events, such as heart attack,

stroke, heart failure and cardiovascular death. Manufacturers also state that mortality data

are collected routinely during clinical trials. Supplementary documentation from the man-

ufacturers (Boston Scientific, St. Jude Medical, Covidien and Medtronic) indicates that

they either plan their first randomised trial or an additional randomised trial or that they

plan to reportresults from RCTs in the next 1 or 2 years (see Appendix 1).

Safety

Of the 22 studies that were included in the safety assessment, 13 reported procedure-

related complications. The most commonly reported procedure- and device-related com-

plications were of a mild to moderate nature.

Table 1 below provides an overview of harms in terms of total and major adverse events.

Major procedure-related complications were reported in 4 studies. Three studies noted

renal artery dissection on placement of the catheter (0.65% to 9.09%), 1 study reported a

psoas hematoma that was secondary to placement of the catheter (9.09%) and 1 study

described 1 case of respiratory and cardiocirculatory depression due to analgosedation

(1.89%) and 1 case of severe artery spasm that resulted in residual stenosis that had no

hemodynamic relevance (1.89%). Overall, the frequency of major complications was 0.551%.

No intervention-related mortality was reported in any study (C0001).

Six studies (n=315) reported major complications during the follow-up period, that

ranged from 3 months to 2 years. The complications that were considered to be major

were hypertensive episodes that required hospitalisation (5% to 33.3%), hypotensive

events that required hospitalisation (2% to 2.86%), angina (2.04%), transient ischaemic

attacks (2.04%), progression of existing stenosis (0.65% to 2.17%) and hypertensive renal

disease progression (2.17%). None of the studies reported aortic stenosis, thrombosis or

significant structural abnormalities of the renal arteries.

In the Symplicity HTN-2 RCT, major complications appeared during the 6-month follow-

up in 8 of the RDN treated patients (15.4 %) and 5 of the patients that received only

pharmacological medication (9.3%). One RDN patient and 2 control patients suffered a

transient ischaemic attack, and 1 patient from each group developed angina. Additional

serious events that required hospitalisation in patients who underwent RDN included

1 case of nausea and oedema, 1 hypotensive episode, 3 hypertensive emergencies that

were unrelated to non-persistence and 1 hypertensive crisis after clonidine was halted.

Two patients of the control group presented with hypertensive emergencies.

In the RCT with 27 patients that assessed the impact of RDN using the Navistar® Ther-

moCool® catheter plus pulmonary vein isolation (PVI) versus PVI alone, no acute adverse

events or renal artery stenosis were reported at 6 months in either group; the study did

not comment on other post-procedural adverse events (C0001, C0008).

Clinical effectiveness

The most recent high-quality SR that assessed overall mortality reported no deaths during

the follow-up periods and none of the publications in this rapid assessment reported any

cardiovascular mortality (D0001).

Table 1 below provides an overview of the main health benefit based on the evidence

currently available.

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The SR that assessed cardiovascular morbidity from coronary heart disease, stroke, peri-

pheral arterial obstructive disease and heart failure found no relevant studies, and among

the RCTs and non-RCTs that were identified, none examined these outcomes (D0002).

One SR included 1 non-RCT that examined left ventricular hypertrophy in 64 patients 6

months following renal denervation using the Symplicity® system. The mean difference in

left ventricular mass was 23.8 g/m2

(95% CI, 7.4–40.2 g/m2

). This result significantly fa-

vored renal denervation, but the quality of this evidence was very low. Further, 1 non-RCT

(prospective controlled trial) of 46 patients analysed left ventricular hypertrophy 6 months

after renal denervation using Symplicity® but measured left ventricular mass differently.

The mean difference was 3.6 g/m1.7

(95% CI, -3.6–10.8 g/m1.7

), but not significant, and

the quality of this evidence was very low.

Finally, 1 RCT with 27 patients assessed left ventricular hypertrophy after 6 months but used

the Navistar® ThermoCool®. Left ventricular mass (formula not indicated) was 15.4 g/m

lower in patients who had undergone renal denervation (95% CI, 10.8–20.1 g/m). The

mean difference was significant, but the quality of this evidence was very low (D0005).

According to the SR, 3 controlled studies analysed changes in systolic and diastolic BP at

6 months (2 RCTs and 1 non-RCT). The studies included 158 patients in total and used

different types of catheters (1 RCT used the Navistar® ThermoCool®, and the other RCT

and non-RCT used Symplicity®). With renal denervation, there were significant decreases

in systolic BP (mean difference 29.8 mm Hg; 95% CI, 20.6–37.2 mm Hg) and diastolic BP

(mean difference 11.0 mm Hg; 95% CI, 5.7–16.4 mm Hg), and the quality of this evidence

was low. However, on re-analysing the data and grouping studies by catheter type, we

noted that pooling the 2 studies that used the Symplicity® system (131 patients) resulted

in a mean difference in systolic BP of 33.6 mm Hg (95% CI, 25.9–41.3 mm Hg) and a

mean difference in diastolic BP of 13.8 mm Hg (95% CI, 7.3–20.3 mm Hg), both of which

were significant. Here, the quality of the evidence was moderate. The study that used the

Navistar® ThermoCool® in 27 patients reported mean differences in systolic and diastolic

BP of 23 mm Hg (95 % CI, 16.8–29.2 mm Hg) and 7.0 mm Hg (95% CI, 2.5–11.5 mm Hg),

respectively, which were also significant, but the quality of the evidence was very low

(D0006).

One SR identified an RCT with 100 patients that measured changes in renal function in

terms of estimated glomerular filtration rate (eGFR) after 6 months of follow-up using

the Symplicity® system. The mean difference was 0.7 ml/min/1.73m2

and not significant

(95% CI, -5.2–3.8 ml/min/1.73m2

). The quality of this evidence for this outcome was low.

This RCT also examined changes in renal function, based on serum creatinine levels,

after six 6 of follow-up using the Symplicity® system. The mean difference in serum cre-

atinine was 1.3 µmol/L and not significant (95% CI, -4.4–7.0 µmol/L); the quality of this

evidence was also low (D0011).

Applicability of the evidence

A summary table that characterises the applicability of the body of evidence is presented

in Appendix 1, Table 24. Briefly, regarding the population, the inclusion criteria of the

studies appeared to target the intended patient population with treatment-resistant hy-

pertension, but many patientswho were included had higher BP than our inclusion criteria,

and it is possible that real-life use may differ from use in the studies. Moreover, normal

renal nerve anatomy/access is necessary, depending on how the procedure is performed.

Further, with regard to the intervention, the procedure entails the delivery of radiofre-

quency or ultrasonographic energy along the renal arteries to effect denervation, and

there is no immediate method of determining whether the ablation has been successful.

The Symplicity® catheter has been used in most controlled studies, but other systems are

currently being implemented.

Notably, surrogate outcomes were assessed in the studies, whereas clinically relevant end-

points (i.e. overall mortality, cardiovascular mortality and major events, such as stroke,

myocardial infarction and heart failure) have not been analysed. At this stage, no con-

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trolled studies have focused on how RDN affects such outcomes as patient satisfaction,

quality of life and activities of daily living – thus, the full clinical benefit remains unknown.

Reimbursement

RDN is reimbursed in 13 countries in Europe, and in most cases regardless of the type of

device. In the majority of countries, this has been a formal reimbursement decision, i.e.

based on (national) policy. In 1 country, Medtronic’s Symplicity® received conditional cov-

erage. In 5 countries a decision on reimbursement is in process, 2 countries do not re-

imburse RDN, and in 3 countries the reimbursement status is unknown (B0003).

Table 1: Summary of relative effectiveness of renal denervation systems

Treatment-resistant hypertension

Main health benefit* Harm

Change in SBP

at 6 months

(mm Hg)

Change in DBP

at 6 months

(mm Hg)

Change in eGFR

at 6 months

(ml/min/1.73m2

)

Total AEs

(%)

Major AEs

(%)

RDN

Standard

of care

MD = -29.8

[-37.2 - (-20.6)]

(continuous

outcome)

D0006**

MD = -11.0

[-16.4 - (-5.7)]

(continuous

outcome)

D0006

MD = -0.7

[-5.21-3.81]

(continuous

outcome)

D0011

40.4% in the

RDN group

9.3% in the

control group

C0001

15.4% in the

RDN group

9.3% in the

control group

C0001

Quality of

body of

evidence

LOW LOW LOW LOW LOW

NA = not applicable; SBP = systolic blood pressure; DBP = diastolic blood pressure; eGFR = estimated glomerular

filtration rate; AEs = adverse events; MD = mean difference. ** The assessment element ID codes (e.g.

D0001) refer to the result cards in Appendix 2, which gives details on the relevant results.

* This table provides data from the evidence currently available.

Discussion

The published data suggest that RDN is a safe procedure in the short to medium term.

Although RDN can cause visceral pain during the procedure, the pain can be controlled

with sedatives and narcotics, and the technique can be applied without major complica-

tions. The reported rate of major procedure- or device-related complications is low, most

of which are resolved without major complications.

Nevertheless, the reporting of adverse events varies – for example, safety was not in-

cluded as an endpoint, or complications or adverse events were not adequately reported.

One of the main post-procedural complications of RDN are hypotension or hypertension

that can require hospitalisation. These or other indirect complications, such as the ap-

pearance of respiratory and cardiocirculatory depression, related to the control of anal-

gesia and sedation, are underestimated in the included studies.

The follow-up time was inadequate to analyse long-term complications. The detrimental

effects of this invasive procedure on the anatomy of the renal arteries are unknown.

Moreover, information is limited regarding the use of this procedure in patients with im-

paired renal function, and whether these patients are candidates for RDN should be ex-

amined in future studies.

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No conclusion could be drawn from the available evidence regarding overall mortality, as

none of the ongoing studies in this rapid assessment defined mortality as its main re-

search goal. Because none of the studies in this rapid assessment addressed cardiovas-

cular mortality, no conclusion could be drawn for this outcome, either. Moreover, there

was no evidence on cardiovascular morbidity, except for left ventricular hypertrophy.

Although 2 of the 3 studies reported less left ventricular hypertrophy in patients who

had undergone renal denervation using the Symplicity® and Navistar® ThermoCool® sys-

tems compared with patients who had not, the sample sizes were small, and it was not

possible to pool the studies, because left ventricular mass was measured disparately.

The poor quality of the evidence did not allow any definitive conclusions to be drawn.

All 3 controlled studies in the SR included for this outcome recorded significant decreases

in systolic BP (SBP) and diastolic BP (DBP) after 3 (171 patients) and 6 months (158 pa-

tients) of follow-up, thus favouring renal denervation. The quality of the evidence, how-

ever, varied when assessed using GRADE, ranging from very low (1 study of 27 patients

who used the Navistar® ThermoCool® system) to moderate (2 studies of 144 patients

after 3 months of follow-up and 131 patients after 6 months of follow-up using the Sym-

plicity® system).

According to 1 RCT with 100 patients in the SR included for this outcome, there was no

change in kidney function, based on eGFR and creatinine levels, following renal denerva-

tion at the 6-month follow-up, but no definitive conclusion could be drawn, because the

quality of the evidence was low.

Conclusion

The published data suggest that RDN is a safe procedure in the short to medium term.

However, because safety was not considered the main endpoint, it can not be dismissed

that some complications were not adequately reported.

In terms of clinical effectiveness, renal denervation using the Symplicity® system appears

to decrease BP, whereas the effects of other systems on BP are uncertain, because they

have only been examined in trials that included very few patients. The assessment of

other outcomes, including mortality and cardiovascular morbidity, remains inconclusive.

Current RDN experiences are based primarily on the Symplicity® catheter (Medtronic).

The other RDN systems and new versions of RDN systems that have only been assessed

in early trials might differ with regard to ablation mechanisms and catheter size, which

in turn might generate disparate risk profiles, necessitating further research to establish

their safety. There are several ongoing studies in RDN; thus, more data are expected in

the next several years.

With regard to its budgetary impact, renal denervation will be an add-on therapy, leading

to additional health care resource expenditures in the form of the cost of the system, the

training of staff specialists, and the use of hospital radiology services during the proce-

dure.

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LIST OF ABBREVIATIONS

AEs Adverse events

AHA American Heart Association

AHTAPol Agency for Health Technology Assessment in Poland

AIM Association Internationale de la Mutualité

Avalia-t Galician Health Technology Assessment Agency

BP Blood pressure

CI Confidence interval

CMS Centers for Medicare and Medicaid Services

CNAMTS Caisse nationale de l'assurance maladie des travailleurs salariés

COI Conflict of interest

CPME Comité Permanent des Médecins Européens (Standing Committee of European

Doctors)

CR.DK Central Region Denmark

CRD Centre of Reviews and Dissemination

CT Controlled trial

DARE Database of Abstracts of Reviews of Effects

DBP Diastolic blood pressure

eGFR Estimated glomerular filtration rate

EPOC Effective Practice and Organization of Care Group

ESC European Society of Cardiology

ESH European Society of Hypertension

FDA Food and Drug Administration

FinOHTA Finnish Office for Health Technology Assessment/National Institute for Health and

Welfare

GRADE Grading of Recommendations Assessment, Development and Evaluation

GYEMSZI Gyógyszerészeti és Egészségügyi Minöség- és Szervezetfej le sztési Intézet

(National Institute for Quality and Organisational Development in Health Care and

Medicine)

HTA Health technology assessment

HVB Hauptverband der Österreichischen Sozialversicherungsträger (Association of

Austrian Social Insurance Institutions)

ICD International classification of diseases

ICTRP International Clinical Trials Registry Platform

IQWiG Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (Institute for

Quality and Efficiency in Health Care)

ISI Institute of Scientific Information

LBI-HTA Ludwig Boltzmann Institute for Health Technology Assessment

MD Mean difference

mm Hg Millimeter mercury

NHS National Health Service

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NOKC Norwegian Knowledge Centre for the Health Services

Non RCT Non randomised controlled trial

PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCT Randomised controlled trial

RDN Renal denervation

REA Relative effectiveness assessment

RF Radiofrequency

SAG Stakeholder advisory group

SBP Systolic blood pressure

SR Systematic review

WHO World Health Organisation

WP Work package

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1 SCOPE

Description Project scope

Population Patients with treatment-resistant arterial hypertension (defined as persistent

hypertension despite administration of at least 3 antihypertensive drugs in

adequate doses, including a diuretic) with blood pressure ≥ 140/90 mm Hg

(Calhoun 2008; Mancia 2013) and without secondary cause of hypertension.

ICD-10 code: Hypertensive diseases I10–I15

MeSH terms: Hypertension; Blood Pressure

Intended use of the technology: treatment

Intervention Renal nerve ablation and denervation systems

The intervention involves the destruction of efferent sympathetic nerves and

afferent nerves within the wall of the renal arteries to reduce sympathetic nerve

traffic, thereby causing a reduction in blood pressure.

MeSH terms: Denervation; Catheter Ablation; Sympathectomy

Comparison Standard of care (which includes here: no treatment, additional pharmacological

treatment, device-based hypertension therapy and sham treatment)

Mesh terms: Not used in the search strategy and thus not indicated

Rationale: Currently, there is no standard comparator for this new intervention;

thus, we use standard care as the comparator.

It should be noted that all patients continue their treatment with at least

3 hypertensive drugs. Additional intervention or comparator is considered

add-on therapy.

Outcomes Primary outcomes:

Overall mortality

Cardiovascular mortality

Cardiovascular morbidity (stroke, myocardial infarction, heart failure)

Blood pressure (changes in systolic and diastolic blood pressure)

Complications during or after the treatment

Secondary outcomes:

Left ventricular hypertrophy/systolic and diastolic cardiac function

Kidney function

Quality of life

Effect on daily living

Mesh terms: Not used in the search strategyand thus not indicated

Rationale: The outcomes included here are those that arecommonly used in

studies assessing hypertension.

All outcomes, except ‘complications’, which is reported in the ‘safety’ domain,

are reported in the ‘clinical effectiveness’ domain. Renal function is reported in

both the ‘safety’ and ‘clinical effectiveness’ domains.

Study design Efficacy/effectiveness: Systematic Reviews (SRs)/Health Technology

Assessments (HTAs), randomised controlled trials (RCTs) and, if data from

RCTs are lacking or insufficient, prospective, controlled studies

Safety: As with efficacy and including all prospective studies

Languages English, Spanish, French, German, Swedish, Danish, Norwegian

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Deviations from project plan

The following deviations from the final version of the project plan

(available on the EUnetHTA homepage) were made:

1) In response to the manufacturers’ comments, BP was redefined from a secondary out-

come to a primary outcome, because the currently acknowledged primary outcomes

are those that are known to be associated with a reduction in BP.

2) In light of comments from the Stakeholder Advisory Group (SAG) and the public con-

sultation, all available systems for renal denervation/renal nerve ablation were includ-

ed, and research questions were changed accordingly.

3) In response to comments from the SAG and the public consultation, ‘no renal dener-

vation’ was removed as a comparator. Both renal denervation and other interventions

have been clarified as add-on therapies.

4) In addition to the reviewer who was suggested by the authors, a second external

reviewer who was appointed by the SAG was added.

5) The comparison, the Rheos® SystemTM

/baroreceptor stimulation was removed as a

comparator per a suggestion from the public consultation. This comparator was de-

scribed as inappropriate, because it is an experimental therapy that is less developed

than RDN.

6) Although they were initially included in the project plan, the authors decided, after

further consideration, that ethical, organisational, social and legal aspects were be-

yond the scope of this rapid assessment on renal denervation systems. Training is

necessary to perform the procedure, which will be administered in specialist centres

that have access to the proper facilities – a programme that not all hospitals may

want to prioritise. Even if it is not among the most resource – consuming of technol-

ogies, some sort of re-allocation of resources might be necessary. The procedure could

alter the follow-up of patients and shift them between primary and secondary care.

Because organisational and ethical considerations are setting-specific, they should be

considered as part of a local adoption plan rather than in a joint European setting.

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2 HEALTH PROBLEM AND CURRENT USE OF THE TECHNOLOGY

2.1 Methods

Domain framing

No deviation was required from the general scope of the project, according to the final

project plan.

Research questions

Element ID Research question

A0002 What is the precise definition of treatment-resistant arterial hypertension, and

which diagnosis is given according to ICD-10?

A0003 What are the known risk factors for treatment-resistant arterial hypertension?

A0004 What is the natural course of treatment-resistant arterial hypertension?

A0005 What is the burden of treatment-resistant arterial hypertension for the patient?

A0006 What is the burden of treatment-resistant arterial hypertension for society in

terms of prevalence, incidence and costs?

A0007 What is the target population in this assessment?

A0001 For which indication or for what purposes is renal denervation used, and are

there any contraindications?

A0011 What is the expected annual utilisation of renal denervation?

A0024 How is treatment-resistant arterial hypertension currently diagnosed according

to published guidelines and in practice?

A0020 What is the marketing authorisation status of renal denervation systems?

A0021 What is the reimbursement status of renal denervation systems?

Sources

Overall, a basic search was used as the starting point for answering the research ques-

tions. Additional searches were performed for nearly all research questions in PubMed

and Google, and reference lists were searched. Guidelines were searched, as was the WHO

website, with regard to ICD-10. (The following sources were used: Andersson 2013,

Calhoun 2008, Giles 2012, International Statistical Classification of Diseases and Related

Health Problems 10th

Revision (ICD-10) Version for 2010, Jentzer 2013, Mahfoud 2011a,

Mahfoud 2013a, Mancia 2013, Schmieder 2012, Persell 2011.)

Analysis

No analysis was performed. The aforementioned sources were found to be sufficient to

answer the questions. No formal quality assessment of the literature was performed,

other than a critical appraisal of the publisher/institutions behind the literature.

Synthesis

The research questions were answered in plain text/narrative format. Also, figures were

used to answer some questions.

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2.2 Main results

Target population of this assessment (A0007)

The target population is patients who suffer from resistant hypertension, a condition that

is linked to sympathetic nervous system overactivity, involving the kidneys (Schmieder

2012). Patients who are eligible for the intervention can be treated with catheter-based

renal denervation. The goals of the treatment are to prevent hypertensive end-organ dam-

age and reduce cardiovascular morbidity and mortality (Mahfoud 2011a).

The criteria for having the surgical procedure that identify the actual target population

are presented under the ‘Indications and contraindications for renal denervation’ section.

Definition of treatment-resistant arterial hypertension

and diagnosis according to ICD-10 (A0002)

Treatment-resistant hypertension describes a condition in which conventional/traditional

treatment measures are inadequate in treating a patient’s hypertension – this condition

is also described as true or real resistant hypertension. The standard treatment is based

primarily on medical treatment and lifestyle interventions. Resistant hypertension develops

when the appropriate treatment, including lifestyle modifications (regarding, for example,

obesity and sodium intake) and 3 antihypertensive drugs (1 of which is a diuretic), fails

to lower systolic blood pressure (SBP) and diastolic BP (DBP) values to 140 and 90 mm Hg,

respectively. All drug agents should be prescribed at the optimal doses (Calhoun 2008).

Further pseudoresistance (e.g. white-coat hypertension) and secondary causes (caused by

other diseases, primarily renal disease) must be ruled out. With regard to the definitions

and classification of office blood pressure (BP) levels (mm Hg), guidelines from the Euro-

pean Society of Hypertension (ESH) and European Society of Cardiology (ESC) (Mancia

2013) present the following criteria:

Table 2: Classification of office BP levels (mm Hg)

Category Systolic Diastolic

Optimal <120 and <80

Normal 120–129 and/or 80–84

High normal 130–139 and/or 85–89

Grade 1 hypertension 140-159 and/or 90–99

Grade 1 hypertension 160–179 and/or 100–109

Grade 1 hypertension >180 and/or >110

Isolated systolic hypertension >140 and <90

The BP category is defined by the highest systolic or diastolic BP. Isolated systolic hyper-

tension should be graded 1, 2 or 3 according to SBP values in the indicated ranges.

In the WHO ICD-9 coding system, which was replaced by ICD-10 in 1998, “resistant hy-

pertension” was coded 997.91. This classification was omitted in the ICD-10 coding sys-

tem, and now, ’resistant hypertension’ is classified in the category ‘I99: Other and unspec-

ified disorders of circulatory system’ using ICD-10 online, version 2010 (WHO 2013).

The diagnosis and criteria of resistant hypertension with regard to surgical intervention

are described below.

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Known risk factors for treatment-resistant arterial hypertension (A0003)

Resistant hypertension can be real or merely apparent. Apparent or pseudoresistant hy-

pertension is caused, for example, by nonadherence to medication. The ESH and ESC have

divided risk factors for real, or true, resistant hypertension into 5 categories (Mancia

2013):

Lifestyle factors: obesity or large weight gains, excessive alcohol consumption, high

sodium intake

Chronic intake of vasopressors or sodium-retaining substances

Obstructive sleep apnoea

Undetected secondary forms of hypertension

Advanced and irreversible organ damage, particularly when it involves renal function

or leads to a marked increase in arteriolar wall–lumen ratio or a reduction in large ar-

tery distensibility

The American Heart Association (AHA) has identified older age and obesity as the strong-

est risk factors for resistant hypertension (Calhoun 2008). Other characteristics that are

associated with resistant hypertension, as identified by the AHA, are:

High baseline BP

Excessive dietary salt ingestion

Chronic kidney disease

Diabetes

Left ventricular hypertrophy

Natural course of treatment-resistant arterial hypertension

and the burden on the patient (A0004, A0005)

The natural course of resistant hypertension has been inadequately appraised. If untreat-

ed, hypertension will increase the risk of cardiovascular disease, stroke and renal failure.

Patients must frequently face associated cardiovascular risk factors, such as diabetes,

obstructive sleep apnoea and left ventricular hypertrophy (Calhoun 2013).

Normally, the patient does not experience symptoms that are associated with resistant

hypertension (Calhoun 2008). Some patients might experience fatigue, headache or nose-

bleed – symptoms that are related to higher BP.

The burden of treatment-resistant arterial hypertension on society

with regard to prevalence, incidence and costs (A0006)

Overall, the exact prevalence of resistant hypertension is unknown (Calhoun 2008, Persell

2011). It is, however, assumed to be a common clinical condition. Based on the afore-

mentioned risk factors, the prevalence is expected to rise in the older and more obese

population (Jentzer 2013). Jentzer et al. reported in an American population that 5% to

10% of patients with inadequately controlled hypertension have resistant hypertension,

defined as BP above the goal, despite the use of ≥3 antihypertensive drugs at adequate

dosages and combinations (including a diuretic) (Jentzer 2013).

The ESH and ESC report that the prevalence of resistant hypertension ranges from 5% to

30% of the overall hypertensive population but that it is likely less than 10% (Mancia

2013). Persell reports that among U.S. adults with hypertension, 8.9% meets the criteria

for resistant hypertension (Persell 2011). The prevalence of hypertension (all cases) is

estimated to be 30% to 45% of the general population, which increases with older age.

Definitions of BP differ between countries, which should be noted when examining the

prevalence of resistant hypertension (Mancia 2013).

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No study exists on the specific treatment costs or consequences of resistant hypertension

for the health care system or society.

Current diagnostic approach according to published guidelines

and in practice (A0024)

In diagnosing resistant hypertension, attention must first be paid to the finding that most

cases of resistant hypertension originate from multifactorial factors – rarely from a sin-

gle cause (Calhoun 2008; Mahfoud 2013a). The evaluation should verify the diagnosis

of hypertension, excluding pseudoresistant patients (e.g. white-coat hypertension), un-

cover any causes of secondary hypertension and clarify the cardiovascular risk, organ

damage and related clinical conditions. A medical history should be included in the clini-

cal evaluation, as should a family history with regard to hypertension, a physical exami-

nation, laboratory investigations and further diagnostic tests (Mancia 2013). The evalua-

tion of patients with resistant hypertension should be directed toward confirming actual

treatment resistance (Galhoun 2008).

Indications and contraindications for renal denervation (A0001)

An expert consensus document, with contributions from 11 European countries, that

was published in 2013 from the ESC on catheter-based renal denervation is the basis for

the following criteria with which patients should comply before renal denervation is con-

sidered (Mahfoud 2013a):

Office-based systolic BP ≥ 160 mm Hg (≥150 mm Hg for those with type 2 diabetes)

despite use of ≥ 3 antihypertensive drugs at adequate dosages and combinations

(including a diuretic)

Treatment resistance to lifestyle modification

Exclusion of secondary hypertension

Exclusion of pseudoresistance, based on ambulatory BP (average BP > 130 mm Hg or

mean daytime BP > 135 mm Hg)

Preserved renal function [(glomerular filtration rate (GFR) ≥ 45 ml/min/1.73 m2

)]

Eligible renal arteries: no polar or accessory arteries, no renal artery stenosis, no prior

revascularisation

A position paper from the ESH that was published in 2012 (Schmieder 2012) describes

the criteria that are generally consistent with those above. Patients are eligible as fol-

lows:

They have “…(severe) treatment-resistant hypertension defined by office SBP at least

160 mm Hg (> 150 mm Hg in type 2 diabetes) despite treatment with at least 3 anti-

hypertensive drugs of different types in adequate doses, including 1 diuretic, which is

equivalent to stage 2 or 3 hypertension”

Pseudoresistance is excluded

No adherence to drug therapy must be refuted

Persisting high office BP in spite of drug treatment (is) confirmed with home and most

importantly with 24-h ambulatory BP monitoring, since up to one-third of treatment-

‘resistant’ hypertensive patients have normal BP outside the office (false resistant hy-

pertension due to persisting white-coat effect during treatment)

Contributing lifestyle factors are identified, and secondary causes of hypertensionare

screened to attempt to control BP by removal

The following contraindications are described in the papers above:

Previous renal artery intervention (balloon angioplasty or stenting)

Evidence of renal artery atherosclerosis (defined as renal artery stenosis > 50%)

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Presence of multiple main renal arteries in the kidneys or main renal arteries < 4 mm

in diameter or < 20 mm in length

Patients should be in stable clinical condition (renal denervation is not an emergent con-

dition), thus ruling out patients with recent myocardial infarction, unstable angina pector-

is or a cerebrovascular accident within the past 3–6 months (Mahfoud 2013a; Schmieder

2012).

What is the expected annual utilisation of renal denervation? (A0011, A0020, A0021)

The uncertain prevalence and potential number of candidates, based on indications/con-

traindications for renal denervation, render it difficult to estimate its expected annual

utilisation. The data indicate many potential candidates for renal denervation. More ex-

perience with the procedure in relevant candidates will facilitate calculation of theannual

use of renal denervation (A0011).

Questions regarding the marketing authorisation status and reimbursement status of renal

denervation systems will be answered in the next domain, ‘Description and technical char-

acteristics of technology’, specifically in B0003 (A0020, A0021).

2.3 Discussion

The number of candidates for renal denervation is potentially significant. Estimating the

expected utilisation is challenging, possibly due in part because the ICD-10 coding sys-

tem has no designation for ‘resistant hypertension’, despite the increasing recognition

of resistant hypertension as a major clinical entity (Giles 2012). Lacking such a category

allows for variations in the definition, understanding and categorisation of resistant hy-

pertension. Giles et al. have noted the unfortunate development that resistant hyperten-

sion can no longer be classified as it should be with regard to its complexity. Giles con-

tinues to recommend that resistant hypertension must be addressed by adding ‘complexi-

ty’ to the illness codes, making it possible to code ‘resistant hypertension’.

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3 DESCRIPTION AND TECHNICAL CHARACTERISTICS OF THE TECHNOLOGY

3.1 Methods

Domain framing

No deviation was required from the general scope of the project, based on the final project

plan.

Research questions

Element ID Research question

B0001 What is renal denervation and what are the treatment alternatives?

B0002 What are the approved indications and claimed benefits of renal denervation and

the treatment alternatives?

B0003 What is the phase of development and implementation of renal denervation

systems and the treatment alternatives?

B0004 Who performs or administers renal denervation and the treatment alternatives?

B0005 In what context and level of care are renal denervation systems and the treatment

alternatives implemented?

B0008 What kind of special premises are needed to use renal denervation systems and

treatment alternatives?

B0009 What materials are needed to use renal denervation systems and the treatment

alternatives?

B0010 What kind of data and records are needed to monitor renal denervation systems

and the treatment alternatives?

B0011 What kind of registry is needed to monitor the use of renal denervation systems

and treatment alternatives?

Sources

The research questions were answered by using sources from the main search and sup-

plemented by searches in Google for specific information on each RDN system. (The fol-

lowing sources were used: Andersson 2013, CADTH 2013, Caulfield 2012, Fornell 2013,

Gaffney 2013, KONA medical 2013, Mafeld 2013, Mahfoud 2013a, Mancia 2013, Medlat-

est 2013, Medtronic 2013, Wojakowski 2012).

Analysis

No additional analysis was performed on the resulting information.

Synthesis

The research questions were answered in plain text format.

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3.2 Main results

Description of RDN Systems (B0001)

Most renal denervation systems use low-level radio frequency energy to modulate the out-

put of nerves that lie in the renal artery wall and lead into and out of the kidneys, decreas-

ing blood flow and thereby reducing hypertension by deactivating hyperactive nerves,

without affecting other abdominal, pelvic or lower-extremity nerves (CADTH 2013). There

are, however, other systems that use ultrasonography for ablation.

The mechanism by which renal sympathetic denervation improvesthe management of BP

is complex and involves the following factors (Wojakowski 2012):

Decreasing efferent sympathetic signalling to kidneys

Reducing norepinephrine spillover

Natriuresis

Increasing renal blood flow

Lowering plasma renin activity

Decreasing afferent renal signalling and central sympathetic activation

The system’s energy, through radiofrequency (RF) or ultrasonography, increases the local

temperature in a limited area of the vascular wall and effects the ablation of afferent and

efferent sympathetic nerves (Wojakowski 2012).

Currently, there are a number of RDN systems that use various treatment strategies, as

shown in Table 3 below.

Table 3: Renal denervation systems and their manufacturers and regulatory status

Device Manufacturer CE-marked FDA review

Radiofrequency

Symplicity® Medtronic Y N

Marinr® Medtronic N N

EnligHTN™ St. Jude Medical Y N

Vessix V2™ Boston Scientific Y N

OneShot™ Covidien Y N

Iberis™ Terumo Y N

ThermoCool® Biosense Webster N N

Ultrasound

PARADISE™ ReCor Medical Y N

Y = yes; N=no

Most of these systems use RF energy to target sympathetic renal nerves; the ReCor Para-

diseTM

system uses ultrasonography (Mahfoud 2013a).

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Description of the various procedures (B0001)

The catheter is introduced through the femoral artery and, under fluoroscopic control,

threaded into the renal artery lumen. Once the catheter is in place, a series of 4 to 6 RF

treatments are applied in each renal artery to ablate the sympathetic nerves that course

along the outside of the artery (CADTH 2013). The procedure takes 40-60 minutes (Mah-

foud 2013a). The technology behind the delivery of RF ablation, however, is evolving, with

the introduction of devices that improve time efficiency (Mahfeld 2012).

Ultrasonography is being investigated as an alternative to radiofrequency energy that pro-

vides more targeted nerve ablation without the need for direct vessel contact. Currently,

of the ultrasonographic devices, only the PARADISE™ system is CE-marked. Noninvasive

ultrasonography systems are being developed for RDN. A transducer that is positioned

outside of the body delivers targeted ultrasonographic energy that ‘surrounds’ the artery

and treats the nerves in the vicinity of the vessel. The rationale behind creating a focused

energy field around the outside of the artery is that it should effect greater and more

effective ablation that does not impact the arterial walls (KONA medical 2013).

Catheters that are designed to inject therapeutic agents directly and non-systemically

through the renal artery wall, such as the CricketTM

and Bullfrog® micro-infusion catheters

(Mercator MedSystems), are also in development for RDN. The Mercator micro-infusion

catheters are CE-marked in Europe and have been approved by the FDA.

Current practice and other developments for treatment of resistant hypertension

(B0001)

The Task Force for the Management of Arterial Hypertension of the ESH and ESC (Mancia

2013) describes in their guidelines that most patients with resistant hypertension require

more than 3 drugs. In current practice, this drug combination comprises a thiazide diu-

retic, a long-acting calcium channel blocker, an angiotensin-converting enzyme inhibitor

or angiotensin receptor blocker, and a beta-blocker in patients aged under 60 years

(CADTH 2013).

An alternative to drug treatment is carotid baroreceptor stimulation, which entails chronic

electrical field stimulation of carotid sinus nerves by implanted devices. However, it is

recommended that renal denervation and carotid baroreceptor stimulation should be re-

stricted to resistant hypertensive patients who are at particularly high risk, based on the

inefficacy of additional antihypertensive drugs in controlling BP (Mancia 2013).

Approved indications and claimed benefits (B0002)

The ESC’s consensus document states that per existing evidence, patients are eligible for

renal denervation if they have (severe) treatment-resistant hypertension, defined as of-

fice SBP ≥160 mm Hg (≥150 mm Hg in type 2 diabetes), despite treatment with at least 3

types of antihypertensive drugs at adequate doses, including a diuretic (Mahfoud 2013a).

In certain centres, uncontrolled BP values 140/90 mm Hg are taken as the reference

(Mahfoud 2013a). Table 4 below details the criteria that patients should meet before

renal denervation is considered (Mahfoud 2013a):

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Table 4: Criteria patients should meet before renal denervation is considered

Office-based SBP ≥ 160 mmHg (≥150 mm Hg diabetes type 2)

≥3 antihypertensive drugs in adequate dosage and combination (incl. diuretic)

Lifestyle modification

Exclusion of secondary hypertension

Exclusion of pseudo-resistance using ABPM (average BP 130 mm Hg or

mean daytime BP 135 mm Hg)

Preserved renal function (GFR ≥45 ml/min/1.73m2)

Eligible renal arteries: no polar or accessory arteries, no renal artery stenosis,

no prior revascularisation

Renal denervation is claimed to decrease systolic and diastolic BP. The risk of cardiovas-

cular death is halved with every 20-mm Hg decline in systolic BP. Existing RDN trials have

reported an average reduction of approximately 25 mm Hg (Fornell 2013).

Phase of development and implementation (B0003)

One issue with the original Symplicity® catheter was that it necessitated multiple abla-

tions, each one requiring the catheter to be rotated to create a continuous lesion. To

simplify this procedure, St. Jude, Covidien and Boston Scientific developed a new cathe-

ter that was designed to simplify and shorten the procedure. Medtronic is also investi-

gating a next-generation Symplicity® system that is intended to reduce treatment time

(Marinr®) (CADTH 2013).

Of all renal denervation systems, the Symplicity®, OneShot™, EnligHTN™, Vessix™ V2 and

Iberis™ systems are CE-marked in Europe. None of the systems is FDA-approved, but all

are seeking such status (Medlatest 2013). Of the ultrasonography devices that are in

development, only the PARADISE™ system (ReCor Medical) has received the CE mark.

Medtronic’s Symplicity® renal denervation device has a lead of several years over the

other CE-marked systems and was accepted for parallel review in the US in March 2013.

This program allows the Centers for Medicare and Medicaid Services (CMS) to begin con-

sidering its use for national coverage while the FDA completes its review of safety and

efficacy. The parallel review will be based primarily on the results of the Symplicity HTN-3

trial (Gaffney 2013).

Table 5 shows that in 13 countries in Europe, RDN is reimbursed and in most cases re-

gardless of the type of device. Reimbursement is in the majority of countries decided

upon through formal processes, i.e. described in national policy. In one country, Med-

tronic’s Symplicity® received conditional coverage. In 5 countries a decision on reimburse-

ment is in process, 2 countries do not reimburse RDN, and in 3 countries the reimburse-

ment status is unknown.

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Table 5: Reimbursement status of renal denervation in Europe

Country Reimbursement Yes/No technology-specific vs. non-technology-

specific reimbursement

Austria Yes (temporary, formal) All devices

Belgium - (formal: submissions to the

authorities)

All devices

Croatia No -

Denmark Yes (formal) All devices

England - (Commissioning through evaluation;

reimbursement planned to start

in 2014)

All devices

Estland - (application under process) unknown

Finland Yes (as part of hospital fees) All devices

France - (formal: process waits for STIC

results)

All devices

Germany Yes (formal) All devices

Hungary Unknown unknown

Greece Unknown unknown

Italy Yes (formal) All devices

Ireland Yes (decision at local hospital level) All devices

Lithuania Yes (formal) All devices

Malta No -

Netherlands Yes (Conditional Coverage) Currently onlyMedtronic Symplicity® Flex

For other technologies, discussion is

on-going

Norway Yes All devices

Poland - (formal: submissions to the

authorities)

All devices

Portugal Yes (formal) All devices

Serbia Unknown unknown

Slovakia Yes (formal) EnligtHTNTM

and Symplicity® reimbursed

from 01.01.2014

Spain Yes (formal) All devices

Sweden Yes (formal) All devices

Switzerland Yes (formal) All devices

Source: Information on reimbursement status was kindly provided by the EUCOMED Hypertension Working

Group and Medtronic. The information has been cross-checked and updated from WP5 Strand B members.

Answers were received from Croatia, England, Finland, Germany, Hungary, Ireland, Italy, Lithuania, Malta,

Poland and Slovakia.

STIC: Support Programme for Innovative and Costly Techniques

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Pharmaceutical therapy

Several new pharmaceutical therapies for hypertension are being investigated in phase 2

and 3 clinical trials, including drugs with new pharmacological targets (such as dual vas-

opeptidase inhibitors, a dual-acting angiotensin receptor neprilysin inhibitor, endothelin

antagonists, nitric oxide donors and angiotensin vaccines) and novel, fixed-dose drug

combinations (CADTH 2013).

Personnel and technical requirements (B0004, B0005, B0008, B0009, B0010, B0011)

Renal denervation can be performed in a catheterisation laboratory for cardiovascular

interventions (Andersson 2013; CADTH 2013) by interventional cardiologists or radiolo-

gists and angiologists. The ESC recommends that the procedure should be performed by

staff that has been trained in the therapy and is qualified to manage potential complica-

tions, such as acute dissection of renal arteries by stent implantation. Renal denervation

is performed under analgesic or conscious sedation (CADTH 2013). During the procedure,

vital signs must be monitored. The presence of an anaesthesiologist is generally unnec-

essary but is required in certain countries (Mahfoud 2013a) (B0004).

Andersson et al. recommend that primary care physicians and specialists in internal medi-

cine, nephrology, interventional cardiology and radiology should be involved in the selec-

tion of patients (Andersson 2013). Centres that perform >25 renal interventions per year

can be assumed to have the appropriate expertise (B0005, B0008).

The long-term follow-up of RDN-treated patients is similar to the usual care of hyperten-

sive patients and can be performed by specialists in cardiology, internal medicine or neph-

rology, as well as primary care physicians (Andersson 2013).

There will be a slight increase in the demand for functional and morphological diagnos-

tic procedures of the renal arteries (MRI, CT, Doppler-ultrasonography), because they are

part of the routine protocol prior to RDN (Andersson 2013). The CADTH assessment (2013)

concluded that RDN is associated with additional health care expenditures in terms of

the cost of the system, the training of specialist staff, and the use of hospital radiology

services during the procedure, as RDN is currently used as an adjunct to existing thera-

pies for hypertension (B0009).

The Joint UK Societies’ consensus statement on RDN for resistant hypertension (Caulfield

2012) opines that any institution that performs this procedure should have the commit-

ment and ability to include data in a national registry. This stipulation will allow proce-

dural success to be analysed acutely and at the long-term follow-up (Mahfoud 2013a)

(B0010, B0011).

3.3 Discussion

Mahfoud et al. note that BP rarely changes immediately after RDN. It often takes several

weeks to months before a significant decrease in BP occurs, suggesting that sympathetic

neural regulation resets slowly and progressively (Mahfoud 2013a). Further, as currently

implemented, renal denervation is designed to improve BP control in patients whose BP

is resistant to conventional drug therapy. In this regard, renal denervation is unlikely to

significantly reduce pill burden in most patients and is not a cure for hypertension. It is

an add-on therapy, thus leading to additional health care resources to be consumed in

the form of costs of the system, training of specialist staff, and use of hospital radiology

services during the procedure (CADTH 2013).

Although BP has been the primary outcome variable in these studies, several reports sug-

gest that there are beneficial effects in patients with diabetes mellitus, metabolic syn-

drome, cardiac arrhythmias, sleep apnoea and heart failure. In the U.S., once RDN systems

gain FDA market approval, physicians are predicted to begin using them off-label for con-

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ditions other than hypertension (Fornell 2013). In Europe, broadening the indications

might also become an issue, where the devices are only CE-marked and not fixed to a

certain indication.

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4 SAFETY

4.1 Methods

Domain framing

No deviation was required from the general scope of the project, per the final project plan.

Research questions

Element ID Research question

C0001 What are the minor and major adverse events in patients treated with renal

denervation?

C0002 Are there any dose relationships with the adverse effects (e.g. intensity, length

of treatment)?

C0004 What are the potential short- and long-term harms, their frequency and

differences according to setting?

C0005 Are there any susceptible patient groups that are more likely to be harmed?

C0007 Can adverse events be caused by the behaviour of the patients, professionals

or manufacturers?

C0008 What is the safety of renal denervation in relation to the standard of care

(which includes additional pharmacological treatment, device-based therapy

for hypertension and sham treatment)?

Sources

The search domain results were based on a basic systematic literature search

(Appendix 1) and information from the manufacturers. The following sources were used:

Embase (Ovid)

Ovid MEDLINE

ISI Web of Knowledge

Cochrane Library; Cochrane Reviews

Centre for Reviews and Dissemination

WHO ICTRP (International Clinical Trials Registry Platform).

For this domain, all prospective studies that were published in peer review journals were

considered RCTs, non-RCTs and case series. Conference abstracts and proceedings, edi-

torials, opinion papers and unpublished data were excluded.

The studies were selected by 2 independent investigators who were responsible for re-

viewing the abstracts and applying the inclusion/exclusion criteria to determine their

eligibility (see Appendix 1).

Analysis

The sources were sufficient to answer 3 of the questions. No data were available to an-

swer C0002, C0005 or C0007.

Data were extracted by 2 independent investigators, and discrepancies between studies

were resolved by discussion. Data were analysed qualitatively. Risk of bias was assessed

using the Cochrane risk of bias checklist. The characteristics of the included SRs and

single trials with quality assessments, along with ongoing studies that were identified

from the trial registry searches, are presented in Appendix 1.

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Synthesis

The information was synthesised into evidence tables and displayed in plain text format.

Evidence tables and GRADE profile tables are provided in Appendix 1.

4.2 Main results

Included studies (C0001)

The evidence for the safety domain is derived from 3 RCT articles, 3 non-RCT articles and

16 case series studies in 904 patients. For 91 patients, the information could be partially

duplicated. Twenty-six patients in the Mahfoud study (Mahfoud 2011b), 28 patients in

the Ukena study from 2011 (Ukena 2011) and 18 subjects in the Ukena study from 2012

(Ukena 2012) were part of the Symplicity HTN-2 trial (Symplicity HTN-2 2010), and 19

patients in the Mahfoud study (Mahfoud 2012) were included in the Symplicity HTN-1

and Symplicity HTN-2 trials.

In 2 of the 3 RCTs, all of the non-RCTs and 11 of the 16 cases series, the RDN procedure

involved RF ablation that was applied with the Symplicity® catheter (Medtronic, Ardian

Inc.). A total of 784 patients underwent RDN using this system. One RCT of 13 patients

performed the intervention using a Navistar® ThermoCool® Irrigated Tip Catheter (Bio-

sense Webster) (Pokushalov 2012). One case series with 30 patients used the Marinr® RF

ablation catheter (typically used for cardiac ablation) (Prochnau 2012a), 1 with 46 pa-

tients used the EnligHTN® multi-electrode renal denervation system (EnligHTN I trial)

(Worthley 2013) and 1 with 9 patients used the OneShot™ (Covidien) RDN system (RHAS

trial) (Ormiston 2013). One case series with 11 patients administered RDN with Para-

dise™ technology (ReCor Medical), which uses a catheter that emits ultrasonographic en-

ergy (Mabin 2012), and 1 trial with 11 patients did not specify the type of system that was

used (Voskuil 2011).

Frequency of adverse events (C0001)

Of the 22 studies in this assessment, 13 (Symplicity HTN-2 2010, Mahfoud 2011b; Mah-

foud 2012; Symplicity HTN-1 2011; Esler 2012; Mabin 2012;Ukena 2012; Vase 2012; Fon-

tenla 2013; Kaltenbach 2013; Ormiston 2013; Scheurig-Muenkler 2013; Worthley 2013)

reported procedure-related complications. The frequency of complications in each of these

studies is listed in Tables 6 and 7. Complications were classified as procedural or device-

related (Table 6 below) and postprocedural (Table 7 below) and further categorised as

major and minor. This classification is based on the original definitions in the studies.

Adverse events related to the procedure or device

Although it has not been quantified in most studies as an adverse event, RDN frequently

causes diffuse visceral abdominal pain during the procedure that can be adequately con-

trolled with narcotics or anaesthesics (Mahfoud 2011b; Symplicity HTN-1 2011; Hering

2012; Mabin 2012; Prochnau 2012a; Simonetti 2012; Vase, 2012; Fontenla 2013; Worth-

ley 2013). The most commonly reported procedure- or device-related complications were

mild to moderate: hypotensive episodes (1.92% to 55.5%) (Symplicity HTN-2 2010; Esler

2012; Vase 2012; Worthley 2013), femoral artery pseudoaneurysms/hematomas at the

access site (1.5% to 44.4%) (Symplicity HTN-2 2010; Mahfoud 2011b; Mahfoud 2012; Sym-

plicity HTN-1 2011; Ukena 2012, Fontenla 2013; Ormiston 2013; Worthley 2013 ), brady-

cardias (4.35% to 18%) (Symplicity HTN-2 2010; Symplicity HTN-1 2011; Fontenla 2013;

Worthley 2013), series of renal artery spasms (5% to 26%) (Vase 2012; Kaltenbach 2013;

Worthley 2013), transient vagal reactions (3.9% to 11.1%) (Symplicity HTN-1 2011, Ukena

2012; Ormiston 2013; Worthley 2013) and vomiting (2.17% to 11.1%) (Ormiston 2013;

Worthley 2013).

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Other minor periprocedural events in the isolated studies were: haematuria (4.35%) (Worth-

ley 2013), dizziness (3.92%) (Symplicity HTN-1 2011), urine infections (Symplicity HTN-2

2010), paraesthesia (1.92%) (Symplicity HTN-2 2010) and allergic reactions to contrast

medium (1.14%) (Mahfoud 2012). Several studies noted the appearance of minor focal

renal artery irregularities that were not flow-limiting that were attributed to minor spasms

and oedema, but they were not recorded as complications (Symplicity HTN-1 2011; Mabin

2012; Prochnau 2012a; Simonetti 2012; Scheurig-Muenkler 2013).

Major complications that were related to the procedure or device were reported in 4 stud-

ies. Three studies accounted for renal artery dissection on placement of the catheter

(0.65% to 9.09%) (Symplicity HTN-1 2011; Esler 2012; Mabin 2012), 1 study reported a

psoas haematoma that was secondary to placement of the catheter (9.09%) (Fontenla

2013) and 1 study described 1 case of respiratory and cardiocirculatory depression due

to analgosedation (1.89%) and 1 case of severe artery spasm that resulted in residual ste-

nosis that had no haemodynamic relevance (1.89%) (Scheurig-Muenkler 2013). No inter-

vention-related mortality has been reported.

Follow-up adverse events

Nine studies (Symplicity HTN-1 2011; Symplicity HTN-2 2010; Mahfoud 2011b; Mahfoud

2012; Brinkmann 2012; Esler 2012; Mabin 2012; Kaltenbach 2013; Worthley 2013) re-

ported on complications during the follow-up period (maximum of 2 years).

The most common minor complication was decreased BP to below target BP or the devel-

opment of hypotensive symptoms (18.2% to 35.1%) (Mahfoud 2011b, Mahfoud 2012,

Mabin 2012). Other minor complications included oedema (1.92% to 5%) (Symplicity

HTN-1 2011; Symplicity HTN-2 2010; Kaltenbach 2013) and flank pain (2.6%) (Symplicity

HTN-1 2011).

Six studies reported major adverse events during the follow-up (n=315 patients) (Symplici-

ty HTN-2 2010; Esler 2012; Brinkmann 2012, Kaltehbach 2013, Worthey 2013). The

complications that were considered to be major were hypertensive emergencies and

crisis (frequency, 5% to 33.3%) (Symplicity HTN-2 2010; Esler 2012; Brinkmann 2012;

Kaltenbach 2013), hypotensive events that required hospitalisation (2.0% to 2.86%)

(Symplicity HTN-2 2010; Esler 2012; Worthley 2013), angina (2.0%) (Symplicity HTN-2

2010), progression of existing stenosis (0.65% to 2.17%) (Symplicity HTN-2 2010; Sym-

plicity HTN-1 2011; Worthley 2013), transient ischaemic attacks (2.0%) (Symplicity HTN-

2 2010) and hypertensive renal disease progression: (2.17%) (Worthley 2013). None of the

studies reported aortic stenosis, thrombosis or important abnormalities.

Susceptible patient groups (C0005)

Patients with chronic renal disease might be more susceptible to RDN-related complica-

tions. All initial RCTs and other included studies restricted the inclusion criteria to patients

who had an estimated GFR (eGFR) ≤45 ml/min/1.73 m2

. Only 1 of the included studies

(Hering 2012) evaluated patients with moderate to severe renal disease (stage 3-4), find-

ing no significant alteration in renal function, based on GFR according to serum creati-

nine or cystatin C levels and per plasma creatinine, cystatin C or urea levels. Scheurig-

Muenkler et al. reported 2 patients with end-stage renal disease and 1 patient with chronic

renal failure who received RDN and did not show any exacerbation in renal function

(Scheurig-Muenkler 2013). In the series by Prochnau et al, serum creatinine and protein-

uria, used as markers of renal function, remained unchanged in 4 patients with chronic

renal insufficiency (Prochnau 2012a).

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Comparison with standard care (C0001, C0008)

The Symplicity HTN-2 RCT (Symplicity HTN-2 2010) reported that 40.3% of patients (n= 21)

who were treated with RF ablation suffered minor and major complications versus 9.26%

of those who received only pharmacological medications (n=5). The majority of adverse

events in the RDN group was related to the procedure or device. During the 6-month

follow-up, major complications appeared in 16.3% (n=8) and 9.8% (n=5) of patients, re-

spectively. One RDN patient and 2 control patients suffered a transient ischaemic attack,

and 1 patient from each group developed angina. Additional serious events that required

hospitalisation in RDN-treated patients included 1 case of nausea and oedema (n=1),

1 hypotensive episode (n=1), 3 hypertensive emergencies that were unrelated to nonper-

sistence with drugs and 1 hypertensive crisis after clonidine was halted. Two control

groups presented with hypertensive emergencies. Renal function, as assessed by serum

creatinine, eGFR, and cystatin C concentrations, were unchanged from baseline in both

groups at 6 months.

In the extension of the Symplicity HTN-2 trial (Ukena 2011), the authors reported that

RDN was performed without any major adverse events in all patients (37 interventions

and 9 controls) but did not provide results on overall complications. Mahfoud (Mahfoud

2011b) observed that 1 patient from the RDN-treated group (n=37) developed a pseudo-

aneurysm of the femoral artery site (2.7%) and that after 3 months, 13 patients experi-

enced hypotension that was associated with symptoms (35%). Two patients who received

only pharmacological medication (n=13) presented with signs or symptoms that were

consistent with hypertension (15.4%).

In 2012 (Mahfoud 2012), Mahfoud noted that RDN was performed without any complica-

tions in 97% of patients (n=110) – 2 patients developed a pseudoaneurysm of the femo-

ral artery site (2.27%), and 1 experienced an allergic reaction to the contrast medium

(1.14%). During the 6-month follow-up, the antihypertensive drug regimens had to be

reduced in 18 patients (18%) and increased in 7 subjects due to the development of symp-

toms. Mean cystatin C, eGFRand urinary albumin excretion remained unchanged after

RDN in all studies. No abnormalities of the renal arteries (significant artery stenosis or

aneurysms) were observed during the study period.

In the RCT that assessed the impact of renal artery denervation (Navistar® ThermoCool®

catheter) that was added to pulmonary vein isolation (PVI) versus PVI alone, no acute

adverse events or renal artery stenosis was reported in either group at 6 months; the

study did not comment on other postprocedural adverse events (Pokushalov 2012).

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Table 6: Frequency of procedure- or device-related adverse events in the included studies

Author, date Study

type N

Minor adverse events, n (%) Major adverse events, n (%) Total

adverse

events

n (%)

Hypo-

tensive

events

Femoral artery

pseudo-

aneurysm/

Haematoma

BC

Renal

artery

spasms

TVR Other Total

Renal

artery

dissection

Psoas

haematoma

Respiratory

and CP

depression

Severe

artery

spams

Total

Symplicity HTN-2 2010 RCT 52 1 (1.92%) 1 (1.92%) 7 (13.46%) 0 0 3 (5.77%) 12 (23.08%) 0 0 0 0 0 12 (23.08%)

Ukena 2011 RCT 37 0 0 0 0 0 0 0 0 0 0 0 0 0

Pokushalov 2012 RCT 13 0 0 0 0 0 0 0 0 0 0 0 0 0

Mahfoud 2011b Non RCT 37 0 1 (2.70%) 0 0 0 0 1 (2.70%) 0 0 0 0 0 1 (2.70%)

Brandt 2012a Non RCT 110 0 0 0 0 0 0 0 0 0 0 0 0 0

Mahfoud 2012 Non RCT 88 0 2 (2.27%) 0 0 0 1 (1.14%) 3 (3.41%) 0 0 0 0 0 3 (3.41%)

HTN1 2011 Case series 153 0 3 (1.96%) 15 (9.80%) 0 6 (3.92%) 0 24 (15.69%) 1 (0.65%) 0 0 0 1 (0.65%) 25 (16.34%)

Voskuil 2011 Case series 11 0 0 0 0 0 0 0 0 0 0 0 0 0

Brinkmann 2012 Case series 12 0 0 0 0 0 0 0 0 0 0 0 0 0

Esler 2012* Case series 35 1 (2.86%) 0 0 0 0 0 1 (2.86%) 1 (2.86%) 0 0 0 1 (2.86%) 2 (5.71%)

Hering 2012 Case series 15 0 0 0 0 0 0 0 0 0 0 0 0 0

Mabin 2012 Case series 11 0 0 0 0 0 1 (9.09%) 1 (9.09%) 1 (9.09%) 0 0 0 1 (9.09%) 2 (18.2%)

Prochnau 2012a Case series 30 0 0 0 0 0 0 0 0 0 0 0 0 0

Simonetti 2012 Case series 5 0 0 0 0 0 0 0 0 0 0 0 0 0

Ukena 2012 Case series 136 0 2 (1.47%) 0 0 8 (5.88%) 0 10 (7.35%) 0 0 0 0 0 10 (7.35%)

Vase 2012 Case series 9 5 (55.56%) 0 0 1 (11.11%) 0 0 6 (66.67%) 0 0 0 0 0 6 (66.67%)

Zuern 2012 Case series 11 0 0 0 0 0 0 0 0 0 0 0 0 0

Fontenla 2013 Case series 11 0 1 (9.09%) 2 (18.18%) 0 0 1 (9.09%) 4 (36.36%) 0 1 (9.09%) 0 0 1 (9.09%) 5 (45.45%)

Kaltehbach 2013 Case series 20 0 0 0 1 (5%) 0 0 1 (5%) 0 0 0 0 0 1 (5%)

Ormiston 2013** Case series 9 0 4 (44.44%) 0 0 1 (11.11%) 4 (44.44%) 9 (100%) 0 0 0 0 0 9 (100%)

Scheurig-Muenkler

2013

Case series 53 0 0 0 0 0 2 (3.77%) 2 (3.77%) 0 0 1 (1.89%) 1 (1.89%) 2 (3.77%) 4 (7.55%)

Worthley 2013 Case series 46 3 (6.52%) 8 (17.39%) 2 (4.35%) 12 (26.09%) 3 (6.52%) 4 (8.70%) 32 (69.57%) 0 0 0 0 0 32 (69.57%)

* Only crossover group patients included. **Article refers to adverse events and specifies that they were mostly periprocedural.

BC: bradycardia; CP: cardiopulmonary; RCT: randomised controlled trial; TVRs: transient vagal reactions

Table 7: Frequency of follow-up adverse events in the included studies

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Author, date Study type N* Follow up

(months)

Minor complications, n (%) Major complications, n (%)

Total

n (%) Hypotensive

events Other Total

Nausea

and/or

oedemas

Hypertensive

episodes

(hospital

admission)

Hypotensive

episodes

(hospital

admission)

Angina

Transient

ischaemic

attack

Progress

of existing

stenosis

Progress

of renal

disease

Total

Symplicity HTN-2

2010

RCT I:49

C:51

6 0

0

0 0

0

1 (2.0%)

0

4 (8.2%)

2 (3.92%)

1 (2.0%)

0 (0%)

1 (2.0%)

1 (1.96%)

1 (2.0%)

2 (3.92%)

1 (2.0%)

0 (0%)

0 (0%)

0 (0%)

9 (18.3%)

5 ((9.8%)

9 (18.3%)

5 (9.8%)

Ukena 2011 RCT I:37

C:9

3 0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Pokushalov 2012 RCT I:13

C:14

12 0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Mahfoud 2011b Non RCT I: 37

C:13

3 13 (35.1%)

0

0

0

13 (35.1%)

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

13 (35.1%)

0

Brandt 2012a Non RCT I:110

C: 10

6 0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Mahfoud 2012 Non RCT I:88

C:12

6 18 (20.4%)

0

0

0

18 (20.4%) 0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

18 (20.4%)

0

HTN1 2011 Case series 153 24 0 4 (2.61%) 4 (2.61%) 0 0 0 0 0 1 (0.65%) 0 1 (0.65%) 5 (3.3%)

Voskuil 2011 Case series 11 1 0 0 0 0 0 0 0 0 0 0 0 0

Brinkmann 2012 Case series 12 6 0 0 0 0 4 (33.3%) 0 0 0 0 0 4 (33.3%) 4 (33.3%)

Esler 2012 Case series 35 12 0 0 0 0 2 (5.7%) 1 (2.86) 0 0 0 0 3 (8.57%) 3 (8.57%)

Hering 2012 Case series 15 12 0 0 0 0 0 0 0 0 0 0 0 0

Mabin 2012 Case series 11 3 2 (18.2%) 0 2 (18.2%) 0 0 0 0 0 0 0 0 2 (18%)

Prochnau 2012a Case series 30 12 0 0 0 0 0 0 0 0 0 0 0 0

Simonetti 2012 Case series 5 2 0 0 0 0 0 0 0 0 0 0 0 0

Ukena 2012 Case series 136 6 0 0 0 0 0 0 0 0 0 0 0 0

Vase 2012 Case series 9 1 0 0 0 0 0 0 0 0 0 0 0 0

Zuern 2012 Case series 11 24 0 0 0 0 0 0 0 0 0 0 0 0

Fontela 2013 Case series 11 6 0 0 0 0 0 0 0 0 0 0 0 0

Kaltehbach 2013 Case series 20 6 0 2 (10%) 2 (10%) 0 1 (5%) 0 0 0 0 0 1 (5%) 3 (15%)

Ormiston 2013 Case series 9 12 0 0 0 0 0 0 0 0 0 0 0 0

Worthley 2012 Case series 46 6 0 0 0 0 0 1 (2.17%) 0 0 1 (2.17%) 1 (2.17%) 3 (6.5%) 3 (6.5%)

* Patients for whom follow-up information was available

RCT: randomised controlled trial

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4.3 Discussion

Published data suggest that RDN is safe in the short to medium term. Although RDN can

cause visceral pain during the procedure, it is usually controlled with sedatives and nar-

cotics, and the technique appears to be able to be applied without major complications.

The reported rate of major complications that were related to the procedure or device

was very low, most of which were resolved without major implications.

The reported frequency of adverse events varied widely (0% to 40.38%) in the included

studies. In 2 of the RCTs (Ukena 2011; Pokushalov 2012), all non-RCTs (Mahfoud 2011b;

Mahfoud 2012; Brandt 2012a) and many case series, safety was not considered the main

endpoint, and complications and adverse events were incompletely reported (Voskuil 2011;

Brinkmann 2012; Hering 2012; Ukena 2012; Zuern 2012; Prochnau 2012a; Fontenla 2013;

Kaltehbach 2013). Often, the authors referred to the nonexistence of severe/major proce-

dure-related complications or adverse events without defining a ‘severe adverse event’ or

commenting on postprocedural adverse events, hampering interpretation of the evidence

with regard to safety and making it impossible to perform a pooled analysis of the data.

One of the main complications of RDN in certain studies is the unwanted effects on

postprocedure BP, which can result in hypotensive or hypertensive episodes that require

hospitalisation. These or other indirect complications, such as the appearance of respira-

tory and cardiocirculatory depression that was related to the control of analgesia and

sedation in Scheurig-Muenkler (Scheurig-Muenkler 2012), could have been underestimat-

ed in the included studies, which should be confirmed in adequately designed trials.

Based on the available evidence, it is impossible to draw any conclusions with respect to

the frequency of follow-up complications (C0001).

The follow-up length was inadequate to analyse long-term complications. Concerns and

doubts with regard to the aggravation of renal disease with RDN remain unresolved (Mah-

foud 2011b; Mahfoud 2012). The Symplicity HTN-2 study and several other trials that

analysed renal function (Symplicity HTN-2 2010; Esler 2012; Pokushalov 2012; Mahfoud

2011b; Mahfoud 2012; Prochnau 2012a; Fontenla 2013; Kaltenbach 2013; Ormiston 2013)

reported no changes in eGFR, cystatin C or other parameters that are used to measure

renal failure function in the 3-12 months of follow-up. However, in the Symplicity HTN-1

trial, with an extended follow-up of 24 months, eGFR remained stable in the first several

years but fell dramatically in 10 patients who were followed for 2 years. Whether these

disparities are attributed to differences in the study population or BP or the detrimental

effect of renal denervation requires clarification, for which longer-term assessments are

needed (C0001).

There is uncertainty regarding the harmful effects of RDN on the anatomy of the renal

arteries. Mild, hemodynamically irrelevant wall irregularities, corresponding to small lo-

cal spasms or circumscribed wall oedema, were seen consistently after RDN, but they did

not limit blood flow. Several of the studies (Esler 2012; Pokushalov 2012; Mahfoud 2011b;

Mahfoud 2012; Symplicity HTN-1 2011; Prochnau 2012a; Fontenla 2013; Kaltenbach 2013)

performed magnetic resonance angiography, computed tomographic scan and/or renal

ultrasonography during the follow-up period and ruled out the appearance of renal ar-

tery aneurysms, stenosis, thrombosis and any other relevant vascular abnormalities in the

short to medium term (6-12 months), but the evolution of the renal arteries over the long

term is unknown (C0001).

Information is limited regarding the use of RDN in patients with impaired renal function.

Most patients who were treated in the initial RCTs and other included studies had an

eGFR ≤45 ml/min/1.73 m2

and preserved renal function. Hering et al. suggested that renal

function remains unaltered in patients with moderate to severe renal disease (stage 3-4),

but their study was limited by the design (case series) and the small sample size (Hering

2012). Scheurig-Muenkler et al. also noted that 2 patients with end-stage renal disease

and 1 patient with chronic renal failure did not exhibit any exacerbation in renal function

(Scheurig-Muenkler 2013), whereas Prochnau et al. reported that renal function remained

unchanged in 4 patients with chronic renal insufficiency (Prochnau 2012a). Whether these

patients are candidates for RDN should be determined in future studies (C0005).

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Current RDN experiences are based primarily on the Symplicity® catheter (Medtronic,

Ardian Inc.). The other RDN systems and new generations of RDN systems have been as-

sessed only in preliminary trials that have included few patients. Because these systems

do not use exactly the same ablation mechanisms and because the diameter of the cath-

eter can differ, they might have disparate risk profiles. These systems require further eval-

uation to establish their safety.

In summary, the evidence on the safety of RDN systems is compromised by the following

methodological limitations, preventing firm conclusions from being drawn regarding this

procedure:

Most studies had small sample sizes and large overlaps of patients.

Safety was not the primary endpoint in the majority of studies.

In many studies, RDN was conducted in highly select patients by a small group of

trained health professionals, which does not exclude the possibility of serious adverse

effects if the technique is to be performed routinely in clinical practice.

Possibility of bias due to lack of blinding.

Large heterogeneity in individual responses to RDN.

Short follow-up, which means that there is a lack of knowledge about the long-term

potential of nerve fibre regeneration and the occurrence of long-term adverse effects.

Potential conflicts of interest in most included studies due to their being financed by

the manufacturer of the device in question and/or participation in research studies by

the company’s investigators (see evidence tables in Appendix 1).

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5 CLINICAL EFFECTIVENESS

5.1 Methods

Domain framing

No deviation was required from the general scope of the project, per the final project plan.

The research questions for assessing the clinical efficacy of renal denervation systems

are listed in the table below.

Endpoints for determining clinical effectiveness were derived from the 3 main categories

of endpoints – ‘mortality’, ‘morbidity’ and ‘quality of life’ – as defined in the EUnetHTA

guideline on clinical endpoints [see European Network for Health Technology Assess-

ment (EUnetHTA). Endpoints used for relative effectiveness assessment of pharmaceuti-

cals: clinical endpoints: EUnetHTA; 2013a.].

Research questions and evidence found for each question

Element

ID

Research

question

Outcomes

(PICO/scope)

Assessed by

(references and study design)

D0001 What is the effect of renal denervation

on overall mortality?

Overall mortality Davis 2013 (SR)

D0002 What is the effect of renal denervation

on cardiovascular mortality?

Cardiovascular

mortality

No SR or RCT or non-RCT found

D0005 How does renal denervation affect

symptoms and findings?

Cardiovascular

morbidity

Cardiovascular morbidity in terms

of coronary heart disease, stroke,

peripheral arterial obstructive

disease, heart failure:

Andersson 2013 (SR)

Left ventricular hypertrophy:

Andersson 2013 (SR)

Mahfoud 2013b (non-RCT)

Pokushalow 2012 (RCT)

D0006 How does renal denervation affect

progression of treatment-resistant

arterial hypertension?

Blood pressure Davis 2013 (SR)

Ahmed 2012 (RCT)

D0011 What is the effect of renal denervation

on patients’ body functions (e.g.

kidney function)?

Kidney function Gosain 2013 (SR)

D0016 How does the use of renal denervation

affect activities of daily living?

Exercise Exercise capacity reported as

maximum work load and peak

oxygen uptake (VO2

peak)

Ukena (RCT) 2011

D0012 What is the effect of renal denervation

on generic health-related quality of life?

Quality of life No SR or RCT or non-RCT found

D0013 What is the effect of renal denervation

on disease-specific quality of life?

Quality of life No SR or RCT or non-RCT found

D0017 Were patients satisfied overall with

renal denervation?

Quality of life No SR or RCT or non-RCT found

D0018* Would the patient be willing to

undergo renal denervation?

Quality of life No SR or RCT or non-RCT found

D0023* How does renal denervation modify

the need for other technologies and

use of resources?

Activities of daily

living (Decrease in

number of

medications)

Gosain 2013 (SR)

* These assessment elements were added since they were included in the first pilot (EndoBarrierTM

).

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In terms of mortality, we considered overall mortality and cardiovascular mortality.

With regard to morbidity, we defined morbidity as cardiovascular morbidity (stroke, my-

ocardial infarction and heart failure), changes in BP, left ventricular hypertrophy and

change in ejection fraction (volume). For function, renal function (body function) and BP

during exercise (activities of daily life) were assessed. Health-related quality of life and

patient satisfaction were also examined, as was change in management (decrease in

number of medications).

Sources

To answer the research questions in this domain, we used the results from a basic sys-

tematic literature search of the following sources (see Appendix 1: Documentation of

search strategy):

Biomedical databases (Medline via Ovid, Embase)

Cochrane database, DARE and HTA databases via the Cochrane Library and CRD

The ISI database

Manual searches, including articles provided by the manufacturers

WHO search portal ICTRP for identifying registered clinical trials

The relevant literature was selected by 2 people independently (see Appendix 1 for study

selection). In terms of study design, SRs/HTAs, RCTs and, if data from RCTs were lack-

ing or insufficient, prospective, controlled studies were selected to answer questions re-

lated to this domain. In cases in which more than 1 SR was available, the high-quality SR

that assessed 1 or more of the predefined outcomes most recently was included.

Analysis

The sources were sufficient to answer the questions [i.e. it was sufficient (or feasible) to

simply retrieve information from 1 of the sources, and it was not necessary to perform

additional analyses, such as an indirect comparison].

To assess the quality of the SRs, the English version of the NOKC checklist for systematic

reviews, adapted from the Cochrane EPOC group appraisal list for systematic reviews

(Grimshaw 2003), was used (NOKC SR checklist 2013). The quality of the single studies

was determined using the Cochrane risk of bias checklist for RCTs (Higgins 2011). The

characteristics of the SRs and single trials with quality assessments and ongoing studies

that were identified from the trial registry searches are presented in Appendix 1.

Quality of evidence was assessed using the GRADE instrument (GRADE 2004) and classi-

fied as high (i.e. “We are very confident that the true effect lies close to that of the esti-

mate of the effect”), moderate (i.e. “We are moderately confident in the effect estimate:

the true effect is likely to be close to the estimate of the effect, but there is a possibility

that it is substantially different”), low (i.e. “Our confidence in the effect estimate is lim-

ited: the true effect may be substantially different from the estimate of the effect”) or

very low (i.e. “We have very little confidence in the effect estimate: the true effect is likely

to be substantially different from the estimate of the effect”). When appropriate, meta-

analyses were performed using RevMan (version 5.2, available for download from

http://ims.cochrane.org/revman). All reporting was done per the Preferred Reporting Items

for Systematic Reviews and Meta-Analyses (PRISMA Statement 2012).

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Synthesis

Research questions were answered in plain text format with reference to the GRADE evi-

dence tables in Appendix 1.

5.2 Main results

Included studies

In evaluating clinical effectiveness, we included 3 SRs (Davis 2013; Gosain 2013; Anders-

son 2013) and 4 controlled studies – 3 RCTs and 1 non-RCT (Pokushalov 2012; Ukena

2011; Mahfoud 2013b; Ahmed 2012). The SRs and CTs were identified through literature

searches (see flow charts in Appendix 1). All SRs were published within the last year, but

additional results have since been published for some outcomes. Details of the included

publications are shown in the ‘Evidence tables for the ‘safety’ domain’ below.

In general, the SRs had slightly different inclusion criteria, but all searched for controlled

trials. Irrespective of how the individual studies were identified, all studies included pa-

tients with resistant hypertension, and RDN was compared with no (or sham) treatment

and pharmacological treatment for hypertension. One study assessed the impact of renal

artery denervation, added to PVI, in patients with a history of atrial fibrillation and drug-

resistant hypertension (Pokushalov 2012).

Controlled studies implemented a follow-up period of 3 to 12 months. We rated the SRs as

high-quality. Individual studies were assessed by the authors using the Cochrane risk of

bias checklist for RCTs (Higgins 2011) or the Newcastle-Ottawa scale (Pokushalov 2012)

in the SR by Davis et al. (Davis 2013). All scored well with regard to bias within their

study type.

Mortality (D0001, D0002)

The SR by Davis et al. was the most recent SR with high quality that assessed overall

mortality (Davis 2013). Davis et al. reported that no deaths occurred during the stipulated

follow-up periods. In terms of cardiovascular mortality, none of the identified publica-

tions in this rapid assessment addressed this outcome.

Morbidity (D0005, D0006)

Cardiovascular morbidity

The SR by Andersson et al. examined cardiovascular morbidity in terms of coronary heart

disease, stroke, peripheral arterial obstructive disease and heart failure but failed to

identify any studies reporting on these outcomes (Andersson 2013). Among the RCT and

non-RCTs (prospective controlled trials), none assessed these outcomes. The SR by An-

dersson et al. included 1 non-RCT that reported left ventricular hypertrophy in 64 pa-

tients 6 months following renal denervation using the Symplicity® system (Brandt 2012b).

The mean difference in left ventricular mass was 23.8 g/m2

. This result significantly fa-

voured renal denervation, but the quality of the evidence was very low. Moreover, 1 non-

RCT of 46 patients assessed left ventricular hypertrophy 6 months after renal denerva-

tion using Symplicity® (Mahfoud 2013b) but measured left ventricular mass differently;

the mean difference was 3.6 g/m1.7

and not significant. The quality of this evidence was

very low.

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Finally, 1 RCT with 27 patients (13 in the intervention group and 14 in the control group)

assessed left ventricular hypertrophy after 6 months but used the Navistar® Thermo-

Cool® system (Pokushalov 2012). Left ventricular mass index (formula was not indicat-

ed) was 15.4 g/m lower in patients who had undergone renal denervation. The mean

difference was significant, but the quality of this evidence was very low (D0005).

Blood pressure

The SR by Davis et al. was the most recent high-quality SR that examined changes in BP

(Davis 2013). This group stated that once full articles were retrieved, studies were ex-

cluded if there was an overlap in patients with another study in the same analysis (in

which case the study with the largest sample size was selected). Thus, overlaps between

patient groups were avoided in the meta-analyses.

Three controlled studies assessed changes in SBP and DBP at 6 months (2 RCTs and 1 non-

RCT). They included a total of 158 patients and used different types of catheters (1 RCT

used the Navistar® ThermoCool® and 1 RCT and 1 non-RCT used the Symplicity® system)

(Pokushalov 2012; Symplicity HTN-2 Investigators, Esler 2010; Krum 2009). Renal denerva-

tion effected a significant decrease in SBP, with a mean difference of 29.8 mm Hg (95% CI,

20.6–37.2 mm Hg), and a significant decrease in DBP, with a mean difference of 11.0

mm Hg (95% CI, 5.7–16.4 mm Hg); the quality of this evidence was low.

When we re-analysed the data and grouped studies by catheter type, pooling the 2 studies

that included 131 patients (75 in the intervention group and 56 in the control group) and

used the Symplicity® system resulted in mean differences in SBP of 33.6 mm Hg (95% CI,

25.9–41.3 mm Hg) and DBP of 13.8 mm Hg (95% CI, 7.3–20.3 mm Hg), both of which

were statistically significant. Here, the quality of the evidence was moderate. The study

that used the Navistar® ThermoCool® system included 27 patients and reported mean

differences in SBP of 23 mm Hg (95% CI, 16.8–29.2 mm Hg) and DBP of 7.0 mm Hg

(95% CI, 2.5–11.5 mm Hg), which were also significant; however, the quality of the evi-

dence was very low (D0006).

Function, quality of life, patient satisfaction and activities of daily living

(D0011, D0016, D0012, D0013, D0017, D0018)

Kidney function

The SR by Gosain et al. (Gosain 2013) identified 1 RCT of 100 patients that measured

changes in renal function in terms of change in eGFR after 6 months of follow-up using

the Symplicity® system (Symplicity HTN-2 Investigators, Esler 2010). The mean difference

between the intervention group and the control group was 0.7 ml/min/1.73m2

and not

significant. The quality of this evidence was low. The same RCT examined changes in renal

function, based on serum creatinine levels after 6 months of follow-up using the Symplicity®

system (Symplicity HTN-2 Investigators, Esler 2010). The mean difference was 1.3 µmol/L

and not significant. The quality of this evidence was also low (D0011).

Exercise

One RCT of 46 patients assessed changes in maximum work rate after 3 months of follow-

up after renal denervation using the Symplicity® system (Ukena 2011). The mean differ-

ence between the intervention group and the control group was 3.0 Watts on the reclin-

ing ergometer and not statistically significant. The quality of this evidence was very low.

The same RCT measured changes in peak oxygen uptake (VO2

peak) 3 months after renal

denervation using the Symplicity® system (Ukena 2011). The mean difference was 1.0 ml/

min/kg and not significant. The quality of this evidence was very low, as well (D0016).

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Quality of life (QoL) and patient satisfaction

There was no documentation on issues that were related to QoL or patient satisfaction

(D0012, D0013, D0017, D0018).

Change in management in terms of decrease in number of medications (D0023)

The SR by Gosain et al. was the most recent high-quality SR to examine changes in man-

agement, expressed as a decrease in the number of medications (Gosain 2013).

Gosain and colleagues narratively summarised the changes in the number of medica-

tions in their included studies (Gosain 2013). They reported that the average number of

antihypertensive medications that was used in most studies was 5 and noted a change in

the number of antihypertensive medications after renal denervation in 9 studies. In 3 stud-

ies, with a total of 236 patients, 10% to 20% (52 patients) required fewer medicines, where-

as 10% to 25% (25 patients) needed more medications. One study reported a decline in

antihypertensive medications in 4 of 5 patients. Further, 3 studies of 129 patients ob-

served a decrease in medications in 15% to 25% of renal denervation -treated patients.

Finally, the remaining studies, totalling 60 patients, reported no change in the number of

medications.

5.3 Discussion

No conclusion could be drawn from the available evidence regarding overall mortality. In

addition, none of the ongoing studies in this rapid assessment listed mortality as its

main research question. Because none of these studies addressed cardiovascular mortal-

ity, no conclusion could be drawn for this outcome, either.

There was no evidence available on cardiovascular morbidity, except for left ventricular

hypertrophy. Although 2 of 3 studies reported less left ventricular hypertrophy in patients

who underwent renal denervation using the Symplicity® and Navistar® ThermoCool® sys-

tems compared with patients who did not, the study samples were small, and it was not

possible to pool the studies, because left ventricular mass was measured disparately. The

poor quality of the evidence did not allow any definitive conclusions to be drawn.

All 3 controlled studies in the SR included for this outcome in this rapid assessment

demonstrated a statistically significant decrease in SBP and DBP after 3 (171 patients)

and 6 months (158 patients) of follow-up after renal denervation, thus favouring this

procedure. The quality of the evidence, however, varied when assessed using GRADE,

ranging from very low (1 study of 27 patients who used the Navistar® ThermoCool® sys-

tem) to moderate (2 studies of 144 patients after 3 months of follow-up and 131 pa-

tients after 6 months of follow-up using the Symplicity® system). Thus, we conclude that

renal denervation using the Symplicity® system decreases BP, whereas the effects of the

Navistar® ThermoCool® system on BP are unknown.

BP is generally accepted as a surrogate endpoint for fatal and nonfatal cardiovascular dis-

eases. However, when considering guidelines for pharmaceutical development, the cur-

rent draft for a new guideline on medical products in the treatment of hypertension

states that “positive effects on mortality and cardiovascular morbidity can only be evalu-

ated properly in large-scale and long-term controlled clinical trials” (EMA 2013). Similar

caution is likely to be reasonable in the development of devices and procedures, as as-

sociations might not be monocausal.

According to 1 RCT of 100 patients in the SR for this outcome, there was no change in

kidney function, based on eGFR and creatinine levels, following renal denervation at the

6-month follow-up, but no definitive conclusion can be drawn, because the quality of the

evidence was low.

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In 1 RCT of 48 patients, there was no change in the activities of daily living in terms of

exercise, based on maximum work rates and peak oxygen uptake, following renal de-

nervation at the 3-month follow-up, but due to the low quality of the evidence, no defini-

tive conclusion could be drawn.

Although data from 9 studies, totalling 430 patients, have suggested that the number of

antihypertensive medications decreases following renal denervation, no conclusions can

be made from this result.

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CONTENT OF APPENDIX

APPENDIX 1: METHODS AND DESCRIPTION OF THE EVIDENCE USED ................................. 51

METHODS ...................................................................................................................................................... 51 Project approach and methodology ...................................................................................................... 51 Documentation of the basic search strategies ...................................................................................... 52 Flow charts of study selection .............................................................................................................. 54 Study selection for the ‘safety domain’ ................................................................................................. 54 Study selection for the ‘clinical effectiveness’ domain ......................................................................... 55

DESCRIPTION OF THE EVIDENCE USED ............................................................................................................ 57 Evidence tables of individual studies included ..................................................................................... 57 Evidence tables and quality assessment for the ‘clinical effectiveness’ domain .................................. 63 Risk of bias tables ................................................................................................................................. 69 GRADE profiles for the different outcomes .......................................................................................... 77 GRADE profiles for ‘safety’ domain .................................................................................................... 77 GRADE profiles for ‘clinical effectiveness’ domain ............................................................................. 77 List of ongoing and planned studies ..................................................................................................... 80 Applicability table ................................................................................................................................ 85

APPENDIX 2: RESULT CARDS .............................................................................................................. 86

HEALTH PROBLEM AND CURRENT USE OF THE TECHNOLOGY ....................................................................... 86 A0001: For which indication or for what purposes is renal denervation used, and are there any

contra-indications? ................................................................................................................. 86 A0002: What is the precise definition of treatment-resistant arterial hypertension and which

diagnosis is given according to ICD-10? ............................................................................... 88 A0003: What are the known risk factors for treatment-resistant arterial hypertension? ..................... 89 A0004: What is the natural course of treatment-resistant arterial hypertension? ............................... 91 A0005: What is the burden of treatment-resistant arterial hypertension for the patient? .................... 92 A0006: What is the burden of treatment-resistant arterial hypertension for society in terms of

prevalence, incidence and costs? ........................................................................................... 94 A0007: What is the target population in this assessment? .................................................................. 95 A0011: What is the expected annual utilization of renal denervation? ............................................... 97 A0020: What is the marketing authorisation status of renal denervation systems? ............................ 98 A0021: What is the reimbursement status of renal denervation systems? ........................................... 99 A0024: How is treatment-resistant arterial hypertension currently diagnosed according to

published guidelines and in practice? .................................................................................. 100 DESCRIPTION AND TECHNICAL CHARACTERISTICS OF TECHNOLOGY .......................................................... 102

B0001: What is renal denervation and what are the treatment alternatives? .................................... 102 B0002: What is the approved indication and claimed benefit of renal denervation and the

treatment alternatives? ......................................................................................................... 105 B0003: What is the phase of development and implementation of renal denervation systems

and the treatment alternatives? ............................................................................................ 106 B0004: Who performs or administers renal denervation and the treatment alternatives? ................. 109 B0005: In what context and level of care are renal denervation systems and the treatment

alternatives used? ................................................................................................................. 110 B0008: What kind of special premises are needed to use renal denervation systems and

treatment alternatives? ......................................................................................................... 112 B0009: What materials are needed to use renal denervation systems and the treatment

alternatives? ......................................................................................................................... 113 B0010: What kind of data and records are needed to monitor the renal denervation systems

and the treatment alternatives? ............................................................................................ 114 B0011: What kind of registry is needed to monitor the use renal denervation systems and

treatment alternatives? ......................................................................................................... 115 SAFETY ........................................................................................................................................................ 117

C0001: What are the adverse events and serious adverse events in patients treated with renal

denervation? ......................................................................................................................... 117 C0002: Are there any dose relationship of the harms (e.g. intensity, length of treatment)? .............. 122 C0004: What are the potential short- and long term harms, their frequency, and differences

according to settings? ........................................................................................................... 123

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C0005: Are there any susceptible patient groups more likely to be harmed? .................................... 124 C0007: Can adverse events be caused by the behaviour of patients, professionals or

manufacturers? ..................................................................................................................... 126 C0008: What is the safety of renal denervation in relation to standard of care (which includes

additional pharmacological treatment, device based therapy of hypertension and

sham treatment)? .................................................................................................................. 127 CLINICAL EFFECTIVENESS ........................................................................................................................... 131

D0001: What is the effect of renal denervation on overall mortality? ............................................... 131 D0002: What is the effect of renal denervation on cardiovascular mortality? .................................. 132 D0005: How does renal denervation affect symptoms and findings? ................................................. 133 D0006: How does renal denervation affect progression of treatment-resistant arterial

hypertension? ....................................................................................................................... 135 D0011: What is the effect of renal denervation on patients’ body functions? .................................... 141 D0016: How does the use of renal denervation affect activities of daily living? ............................... 143 D0012: What is the effect of renal denervation on generic health-related quality of life? ................ 144 D0013: What is the effect of renal denervation on disease-specific quality of life? ........................... 145 D0017: Were patients overall satisfied with renal denervation? ....................................................... 146 D0018: Would the patient be willing to undergo renal denervation? ................................................ 147 D0023: How does renal denervation modify the need for other technologies and use of

resources? ............................................................................................................................ 148

APPENDIX 3: CHECKLIST FOR POTENTIAL ETHICAL, ORGANISATIONAL,

SOCIAL AND LEGAL ASPECTS ................................................................................ 150

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APPENDIX 1: METHODS AND DESCRIPTION OF THE EVIDENCE USED

METHODS

Project approach and methodology

For this pilot rapid assessment, Avalia-t were responsible for assessing the ‘Safety’ domain,

CR.DK for the ‘Health problem and current use of the technology’ and ‘Description and tech-

nical characteristics’ domains. NOKC had the responsibility of assessing the ‘Clinical effec-

tiveness’ domain, compiling all domains into a final report and write a final summary of the

review.

The pilot rapid assessment was based primarily on a basic systematic literature search in the

following sources:

Biomedical databases (Medline via Ovid, Embase)

Cochrane database, DARE and HTA databases via the Cochrane Library and CRD

The ISI database

The WHO search portal International Clinical Trials Registry Platform (ICTRP) to identi-

fy registered clinical trials.

Hand searches including articles from the manufacturers

Relevant articles for the 4 domains were selected by the agency who answered research

questions of the domain they were responsible for. References were included or excluded

according to the PICO-scheme described in the project scope.

In terms of study design, SRs/HTAs, RCTs and, if data from RCTs were lacking or insufficient,

prospective, controlled studies were selected for answering questions related to the domain

‘Clinical effectiveness’, while for questions in the ‘Safety’ domain any prospective study was

included. For the two other domains ‘Health problem and current use of the technology’ and

‘Description and technical characteristics’, no restrictions in terms of study design were ap-

plied.

In cases where questions within the domains ‘Health problem and current use of technology’

and ‘Description and technical characteristics of technology’ and ‘Safety’ could not be an-

swered using the information retrieved from the basic systematic literature search described

above, additional searches within specific information sources (e.g. databases for clinical

guidelines, registries etc.) and, if needed, hand searching were performed.

For assessing the quality of SRs, the English version of the NOKC checklist for systematic

reviews adapted from the Cochrane EPOC group appraisal list for systematic reviews (Grim-

shaw 2003) was used (NOKC SR checklist 2013). The most recently published high quality

SRs which assessed one or more of the predefined outcomes were included. Quality of stud-

ies was assessed using the Cochrane risk of bias checklist for RCTs (Higgins 2011).

From the selected studies (including ongoing studies identified from ICTRP), study character-

istics and results concerning safety and clinical effectiveness were extracted into evidence

tables covering the selected assessment elements for the rapid assessment. When applica-

ble, evidence on clinical effectiveness and safety was assessed by using the Grading of Rec-

ommendations Assessment, Development and Evaluation (GRADE) approach (GRADE 2004).

Reporting of clinical effectiveness and safety data was done according to the Preferred Re-

porting Items for Systematic Reviews and Meta-Analyses (PRISMA Statement 2012).

Assessment elements selected and the translated research questions that were addressed in

the assessment (see domain reports) are primarily based on assessment elements contained

in the document ‘Model for Rapid Relative Effectiveness Assessment of Pharmaceuticals’.

Additionally, assessment elements from other EUnetHTA Core Model Applications (for medi-

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cal and surgical interventions, for diagnostic technologies or for screening) have been

screened and included/merged with the existing questions if deemed relevant.

Documentation of the basic search strategies

Databases: Embase (Ovid), Ovid MEDLINE. Cochrane Library; Cochrane Reviews, DARE,

CENTRAL, Technology Assessments. Centre for Reviews and Dissemina-

tion; DARE, HTA. ISI Web of Knowledge, WHO ICTRP (International Clinical

Trials Registry Platform)

Search date: 2013.06.26

Results: Systematic reviews/ HTA: 26

RCT (CCT): 288

All other study designs (Ovid, ISI) 4807

Databases: Embase 1980 to 2013 Week 25, Ovid MEDLINE(R) In-Process & Other Non-

Indexed Citations and Ovid MEDLINE(R) 1946 to Present

Search date: 2013.06.26

# Searches Results

1 Kidney/ 454231

2 Kidney nerve/ use emez 1714

3 (kidney or renal).ti,ab,kw. 1338605

4 or/1-3 1495229

5 Denervation/ 24253

6 Sympathectomy/ 14911

7 Sympathetic innervation/ use emez 2587

8 Catheter Ablation/ 40219

9 (denervation* or sympathectomy or sympathectomies or sympathetic or innervation* or

(catheter adj2 ablat*)).ti,ab,kw.

253808

10 or/5-9 294316

11 Kidney Denervation/ use emez 1055

12 Kidney Innervation/ use emez 331

13 or/11-12 1328

14 (4 and 10) or 13 19220

15 exp Hypertension/ 648646

16 exp Blood pressure/ 602978

17 (hypertension or hypertensive or blood pressure).ti,ab,kw. 1001917

18 or/15-17 1438668

19 14 and 18 11515

20 Animals/ 7088545

21 Humans/ 27527866

22 20 not (20 and 21) 5180435

23 19 not 22 7699

24 23 use prmz 1927

25 23 use emez 5772

26 remove duplicates from 24 1855

27 remove duplicates from 25 5681

28 limit 26 to "reviews (maximizes specificity)" [SR M] 9

29 limit 26 to "therapy (maximizes specificity)" [RCT M] 81

30 limit 27 to "reviews (maximizes specificity)" [E] 12

31 limit 27 to "therapy (maximizes specificity)" [E] 135

32 28 or 29 or 30 or 31 237

33 26 or 27 7536

34 33 not 32 [no study design filter] 7299

Database: Cochrane Library

Search date: 26/06/13

Description: Cochrane rev. 0

Other reviews 1

HTA 5

Clinical trials 143

Search Name: 2013.06.27 Renal denervation

Date Run: 27/06/13 15:07:10.4

Searches Results

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#1 (kidney or renal):ti,ab,kw 28031

#2 MeSH descriptor: [Catheter Ablation] explode all trees 992

#3 (denervation* or sympathectomy or sympathectomies or sympathetic or innervation* or

catheter near/2 ablat*)):ti,ab,kw

4714

#4 #2 or #3 4714

#5 #1 and #4 225

#6 MeSH descriptor: [Blood Pressure] explode all trees 21962

#7 (hypertension or hypertensive or (blood next pressure)):ti,ab,kw 52626

#8 #6 or #7 52887

#9 #5 and #8 146

Database: CRD DARE and HTA

Search date: 2013.06.26

Results: SR 2, HTA 6

Searches Results

1 MeSH DESCRIPTOR Kidney IN DARE,HTA 71

2 ((kidney or renal)) IN DARE, HTA 1729

3 #1 OR #2 1729

4 MeSH DESCRIPTOR Denervation IN DARE,HTA 17

5 MeSH DESCRIPTOR Sympathectomy IN DARE,HTA 16

6 MeSH DESCRIPTOR Catheter Ablation EXPLODE ALL TREES IN DARE,HTA 223

7 ((denervation* or sympathectomy or sympathectomies or sympathetic or innervation* or

catheter near2 ablation) IN DARE, HTA

340

8 #4 OR #5 OR #6 OR #7 340

9 MeSH DESCRIPTOR Hypertension EXPLODE ALL TREES IN DARE,HTA 450

10 MeSH DESCRIPTOR Blood Pressure EXPLODE ALL TREES IN DARE,HTA 388

11 ((hypertension or hypertensive or "blood pressure") ) IN DARE,HTA 234

12 #9 OR #10 OR #11 1636

13 #3 AND #8 AND #12 8

14 (#13) IN DARE 2

15 (#13) IN HTA 6

ISI Web of Knowledge

Date: 2013.06.26

Search (systematic reviews, HTA):

Topic=(kidney or renal) AND Topic=(denervation or sympathectomy or sympathetic innerva-

tion or catheter ablation) AND Topic=(hypertension or hypertensive or blood pressure) AND

Topic=(systematic* or health technology assessment*)

Search (single studies)

Result: 51

Topic=(kidney or renal) AND Topic=(denervation or sympathectomy or sympathetic innerva-

tion or catheter ablation) AND Topic=(hypertension or hypertensive or blood pressure) AND

Document Types=(Article) AND Topic=(randomi* controlled or controlled clinical or prospec-

tive study or prospective trial) NOT Document Types=(Review)

Search (no study filter)

Result: 987

Topic=(kidney or renal) AND Topic=(denervation or sympathectomy or sympathetic innerva-

tion or catheter ablation) AND Topic=(hypertension or hypertensive or blood pressure) NOT

Topic=(review or randomi* controlled or controlled clinical or prospective study or prospec-

tive trial)

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Flow charts of study selection

Study selection for the ‘safety domain’

Table 8: Flow chart showing selection of studies

Records identified through database

searching (n= 8287)

Records after duplicates removed (n= 4807)

Records screened (n= 4807)

Records excluded (n=4774 )

Full-text articles assessed for eligibility (n= 33)

Studies included in quantitative synthesis (meta-analysis)

(n = 0)

Full-text articles excluded, with rea-sons

(n= 11)

Exclusion criteria are e.g. No safety data (n=6)

Other indication (n=1) Different study design (n=1)

Duplicated data (n=3)

Articles included in qualitative synthesis (n= 22)

RCTs (n=3)

Non randomiszed controlled trials (n=3)

Case series (n=16)

Additional records identified through

other sources (n= 0)

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Study selection for the ‘clinical effectiveness’ domain

Table 9: Flow chart showing selection of SRs

SR/HTA search June 2013: 26 references

26 assessed based on title and abstract

17 excluded for not assessing RDN (15)

and for being unsystematic (narrative)

reviews (2) 9 assessed in full

text

3 excluded for not being SRs (2 for being

meeting abstracts and 1 for being updated

later on)

3 SRs included

9 SRs/HTAs

1SR included (Davis 2013) for being the most recent SR of high quality having assessed mortal-

ity and BP

3 excluded for having all assessed

outcomes updated in a more recent SR

1SR included (Gosain 2013) for being the most recent SR of high quality having assessed kidney function and activity of daily living (ADL)

1 SR included (Andersson 2013) for being the most recent SR of high quality having assessed cardiac morbidity and left ventricu-

lar hypertrophy

3 excluded after quality assessment (1

is a poster with too little information and

2 being issues on emerging technolo-

gies)

Hand search June 2013:

3 full text articles

6 SRs

0 excluded for not being SRs

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Table 10: Flow chart showing selection of controlled trials

Search June 2013: 262 unique references

245 excluded for not assessing RDN or not

being controlled studies based on title

and/or abstract

17 assessed in full

text 10 excluded (3 because we have more

recent information on the same data set, 1

for assessing cost-effectiveness, 1 for being

a protocol, 2 for not assessing outcome

defined by the inclusion criteria, 1 for not

being a controlled study, 1 for being a dupli-

cate reference, 1 for being in language other

than in inclusion criteria)

4 studies included

8 articles

1 study included (Mahfoud 2013b) for additional data on left ventricular

hypertrophy

4 for being covered by one (or more) of

the included SRs

1 article from hand

search

1 study included (Ukena 2011) for function (BP

during exercise)

1 study included (Pokushalov 2012) for additional data on left ventricular

hypertrophy

1 study included (Ahmed 2012) for additional data

on BP

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DESCRIPTION OF THE EVIDENCE USED

Evidence tables of individual studies included

Evidence tables for the ‘safety’ domain

Table 11: Evidence table for RCTs

Author, year,

reference

number

Symplicity HTN-2 Investiga-

tors (2010)

Lancet. 2010;376:1903–9.

Ukena et al. (2011)

J Am Coll Cardiol.

2011;58(11):1176-82.

Pokushalov et al. (2012)

J Am Coll Cardiol 2012;60:1163-70.

Country Europe, Australia, New Zealand Germany, Australia Russia, Netherlands, USA

Declaration

of funding

source and

competing

interests

Funded by Ardian Inc.

Funded by Ardian Inc., Ministry of

Science and Economy of the Federal

State of the Saarland, Deutsche

Hochdruckliga, Deutsche For-

schungsgemeinschaft (KFO 196). An

author is an employee of Medtron-

ic/Ardian Inc.

Two authors have served as consult-

ants with

Medtronic and Biosense Webster. One

author has received research grants

from Medtronic and Biosense-Webster.

One author is an employee of Med-

tronic/Ardian Inc.

Study design RCT RCT RCT

Study objec-

tive

Show that catheter-based RDN

can safely reduce BP in patients

with treatment resistant hyper-

tension

Investigate the effects of RDN on the

cardiopulmonary

response during cardiopulmonary

exercise testing in patients with

resistant hypertension

Assess the impact of RDN added to

pulmonary vein isolation in patients

with a history of AF and drug resistant

hypertension

Intervention RDN and antihypertension

medication

RDN and antihypertension medica-

tion RDN and Pulmonary Vein Isolation

Comparator Only antihypertension medica-

tion Only antihypertension medication Only Pulmonary Vein Isolation

Type of

catheter Symplicity

®

(Ardian, Medtronic) Symplicity®

(Ardian, Medtronic) ThermoCool

®

catheter (Biosense Web-

ster)

Inclusion/

exclusion

criteria

Patients aged 18–85 years with

a systolic BP of 160 mm Hg or

more (≥150 mm Hg in patients

with type 2 diabetes), despite

compliance with ≥ 3 antihyper-

tensive drugs.

Exclusion of estimated eGFR <

than 45 ml/min

per 1.73 m2

, type 1 diabetes,

contraindications to

MRI,substantial stenotic valvular

heart disease, pregnancy, histo-

ry of myocardial infarction,

unstable angina, or CVA in the

previous 6 months

Patients ≥18 years old with an office

BP of ≥ 160 mm Hg (≥ 150 mm Hg

for type 2 diabetic patients), despite

being treated with ≥ 3 antihyperten-

sive drugs (including

a diuretic), with no changes in

medication for a minimum of 2

weeks prior to enrolment

Patients with symptomatic drug-

refractory AF (failure of ≥ 2 class I or

III antiarrhythmic drugs) referred for

catheter ablation (paroxysmal AF with

≥1 monthly episodes or persistant AF)

that present an office-based systolic

BP of ≥160 mm Hg, despite treatment

with ≥ antihypertensive drugs (includ-

ing 1 diuretic) and a eGFR ≥ 45

ml/min/1.73 m2

Number of

patients

Intervention= 52*

Control= 54*

*3 did not attend 6-month

follow-up

Intervention= 37

Control= 9

28 patients included in Symplicity

HTN2 investigators (Lancet 2010)

Intervention: 13

Control: 14

Age (mean)

Total: N/A

Intervention: 58

Control: 58

Total: 60.2± 9.1

Intervention: 59.1± 9.4

Control: 64.9± 6.4

Total: N/A

Intervention: 59.0±11.5

Control: 58.1±13.0

Sex (M/F)

Total:N/A

Intervention: 34M, 18F

Control: 27M, 27FF

Total: 32M, 14F

Intervention: 25M, 12F

Control:7M, 2F

Total: N/A

Intervention: 11 M, 2F

Control: 10 M, 4F

eGFR (ml/min

per 1.73 m2

)

Total: N/A

Intervention: 77 (19)

Control: 86 (20)

Total: 69 ±23

Intervention: 70±24

Control: 64,5±16

Total: N/A

Intervention: 78±6.1

Control: 80.2±4.6

Follow up 6 months 3 months 1 year

AF: atrial fibrillation; CVA: cardiovascular attack; eGFR: estimated glomerular filtration rate; F: female; M: male; MRI: magnetic reso-

nance imaging; N/A: not available; RCT: randomised controlled trial; RDN: renal denervation; mm Hg: Millimeter mercury; min:

minute; ml: milliliter

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Table 12: Evidence table for non RCTs

CVA: cardiovascular attack; DM: diabetes mellitus; eGFR: estimated glomerular filtration rate; F: female; M: male; N/A: not available;

RCT: randomised controlled trial; RDN: renal denervation; RRI: renal resistance index; UAE: urinary albumin excretion; mm Hg: Milli-

meter mercury; min: minute; ml: millilitre

Author,

year,

reference

number

Mahfoud et al. (2011b)

Circulation. 2011;123(18):1940-

6.

Brandt et al. (2012a)

J Am Coll Cardiol. 2012;60(19):1956-

65.

Mahfoud et al. (2012)

Hypertension. 2012;60:419–424.

Country Germany, Australia Germany, Austria Germany, Australia

Declara-

tion of

funding

source

and com-

peting

interests

Funded by Ardian Inc., Ministry

of Science and Economy of the

Federal State of the Saarland,

Deutsche Hochdruckliga,

Deutsche Forschungsgemein-

schaft (KFO 196).

An author is an employee of

Medtronic/Ardian Inc. An author

is supported by an NHMRC

Senior Research Fellowship.

Funded by Ardian Inc.

An author is a consultant from

Medtronic and other author have

received grant support from Med-

tronic.

Funded by Ardian Inc., Ministry of Sci-

ence and Economy of the Saarland,

Deutsche Hochdruckliga, Deutsche

Forschungsgemeinschaft (KFO 196) and

National Health and Medical Research

Council. An author is an employee of

Medtronic/Ardian Inc.

Study

design

Open, non randomised, con-

trolled trial with matched pa-

tients

Open, non randomised, controlled

trial Open, non randomised, controlled trial

Study

objective

Evaluate the relation between

sympathetic activity and glucose

metabolism and the role of

therapeutic RDN

Evaluate the effectof RDN on central

hemodynamic in patients with re-

sistant hypertension

Assess the changes that occur in RRI,

UAE, and renal function after interven-

tional RDN in patients with resistant

hypertension

Inter-

vention

RDN and antihypertension medi-

cation

RDN and antihypertension medica-

tion RDN and antihypertension medication

Compara-

tor

Only antihypertension medica-

tion Only antihypertension medication Only antihypertension medication

Type of

catheter Symplicity

®

(Ardian, Medtronic) Symplicity®

(Ardian, Medtronic) Symplicity®

(Ardian, Medtronic)

Inclusi-

si-

on/Exclusi

on criteria

Patients with an office BP of ≥

160 mm Hg (≥150 mm Hg for

patients with type 2 DM) despite

being treated with at least 3

antihypertensive drugs and a

GFR ≥ 45 ml/min per 1.73 m2

,

Exclusion of pregnant women,

patients with inadequate renal

artery anatomy for intervention,

a history of prior renal artery

interventions, type 1 diabetes

mellitus, myocardial infarction,

unstable angina pectoris, CVA

within the last 6 months, or

hemodynamically significant

valvular disease.

Patients ≥18 years old with an office

BP of ≥ 160 mm Hg (≥ 150 mm Hg

for type 2 diabetic patients), despite

being treated with ≥ 3 antihyperten-

sive drugs (including a diuretic), with

no changes in medication for a

minimum of 3 months prior to en-

rolment

Patients > 18 years with an office BP of ≥

160 mm Hg (≥150 mm Hg for patients

with type 2 DM) despite being treated

with at least 3 antihypertensive drugs

and an eGFR ≥ 45 ml/min per 1.73 m2

,

Exclusion of pregnant women, patients

with inadequate renal artery anatomy for

intervention, a history of prior renal

artery interventions, type 1 diabetes

mellitus, myocardial infarction, unstable

angina pectoris, CVA within the last 6

months, or hemodynamically significant

valvular disease.

Number of

patients

Intervention= 37

Control= 13

26 patients included in Symplici-

ty HTN 2 trial

Intervention= 110

Control = 10

Intervention= 88

Control= 12

19 patients included in Symplicity HTN1

or HTN 2 trial

Age

(mean)

Total: 59.7±1.4

Intervention:58.7±1.6

Control: 62.5±2.9

Total:N/A

Intervention: 63.1 ± 10.2

Control: 63.0 ± 15.3

Total: 61.7 ± 1.0

Intervention: 61.6 ± 1.1

Control: 61.9±3.6

Sex (M/F) Total: 37M, 13F

Intervention: 29M, 8F

Control:8M, 5F

Total:85M, 35F

Intervention: 77M, 33F

Control:8M, 2F

Total:61M, 39F

Intervention: 54M, 34F

Control:7M, 5F

eGFR

(ml/min

per 1.73

m2

)

Total: 76.6±3.1

Intervention: 75.1±3.3

Control: 81.0±7.6

Total: N/A

Intervention: N/A

Control: N/A

Total: 86.1±3.3

Intervention: 84.6±3.6

Control: 97.9_7.4

Follow up

time 3 months 6 months 6 months

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Table 13: Evidence tables for observational studies

Author, year,

reference

number

Symplicity HTN-1 Inves-

tigators (2011)

Hypertension

2011;57:911-7.

Voskuil et al. (2011)

Neth Heart J (2011)

19:319–323.

Brinkmann et al.

(2012)

Hypertension.

2012;60:1485-1490.

Hering et al. (2012)

J Am Soc Nephrol.

2012;23(7):1250-7.

Country Europe, Australia, USA Netherlands Germany, Netherlands Germany, Australia

Declaration of

funding source

and competing

interests

Funded by Ardian Inc.

Three authors are em-

ployees of Medtron-

ic/Ardian Inc.

Not declared

Funded by Deutsche

Forschungsgemein-

schaft

(JO 284/6-1) and Ger-

man Space Agency.

Absence of conflict of

interest.

Funded in part by grants

from the National Health

and Research Council of

Australia and the Victoria

government’s Operational

Infrastructure Support

Program. Various authors

have been investigators in

studies supported by

Medtronic and/or have

received honoraria from

Medtronic and pharma-

ceutical companies. The

Neurovascular Hyperten-

sion & Kidney Disease

laboratory currently

receives research funding

from Medtronic Inc. and

pharmaceutical compa-

nies. Two authors serving

on scientific advisory

boards of Medtronic and

pharmaceutical compa-

nies. An author is an

employee of Medtron-

ic/Ardian Inc.

Study design Case series Case series Case series Case series

Study objective Establish long-term out-

comes of RDN

Report the results of the

first Dutch experience

with RDN

Test the hypothesis

that MSNA reduction is

a typical response to

RDN

Assess short-term renal

safety and efficacy in

patients with concomitant

moderate to severe CKD.

Intervention RDN and antihypertension

medication

RDN and antihypertension

medication

RDN and antihyperten-

sion medication

RDN and antihypertension

medication

Comparator None None None None

Type of cathe-

ter

Symplicity®

(Ardian, Med-

tronic) Not specified

Symplicity®

(Ardian,

Medtronic)

Symplicity®

(Ardian, Med-

tronic)

Inclusion/ex-

clusion criteria

Patients with an office

systolic BP ≥160 mm Hg)

despite taking ≥ 3 antihy-

pertensive drug classes, 1

of which was a diuretic, at

target or maximal toler-

ated dose. Patients were

excluded if they had an

eGFR of < 45 ml/min per

1.73 m2

, type 1 DM or a

known secondary cause

of hypertension other

than sleep apnea or CKD,

or significant renovascu-

lar abnormalities

Patients with office systol-

ic BP ≥ 160 mmHg, de-

spite being treated with

at least three antihyper-

tensive drugs, or con-

firmed intolerance to

medication. Exclusion

criteria: inadequate renal

artery anatomy, pregnan-

cy, age < 18 years, known

secondary cause of hyper-

tension, an eGFR <45

ml/min/1.73 m², type 1

diabetes, haemodynami-

cally significant valvular

disease, implantable

cardioverter defibrillators,

or treatment with

clonidine, moxoni-

dinerilmenidine or warfa-

rin.

Patients with an uncon-

trolled essential hyper-

tension despite treat-

ment with ≥3 antihyper-

tensive medications at

full doses, including a

diuretic.

Exclusion of patients

with secondary hyper-

tension

Patients with resistant

hypertension

and concomitant moder-

ate to severe CKD (stage

3-4)

Number of

patients 153 11 12 15

Age (mean) 57±11 68±12 45-74 61 ± 9

Sex (M/F) 61%M, 39%F 1M, 10F 11M, 1F 9M, 6F

eGFR (ml/min

per 1.73 m2

) 83±20 74±14 N/A 31.2±8.9

Follow up 2 years 1 month 6 months 12 months

CKD: chronic renal disease; DM: diabetes mellitus; eGFR: estimated glomerular filtration rate; F: female; M: male; N/A: not available;

RDN: renal denervation; MSNA: muscle sympathetic renal activity; mm Hg: Millimeter mercury; min: minute; ml: millilitre

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BP: blood pressure; CRF: chronic renal failure; CVA: cardiovascular disease; eGFR: estimated glomerular filtration rate; F: female; M:

male; N/A: not available; RDN: renal denervation; mm Hg: Millimeter mercury; mm:millimeter; cm: centimeter; mg: milligram

Author,

year, refer-

ence num-

ber

Ukena et al. (2012)

Int J Cardiol (2012).

Vase et al. (2012)

Dan Med J.

2012;59:A4439.

Zuern et al. (2012)

Front Physiol.

2012;3:134.

Scheurig-Muenkler et al.

(2013)

Rofo. 2013;185:550–7.

Country Germany Denmark Germany Germany

Declaration

of funding

source and

competing

interests

Funded by Ardian (all

authors have received

per-patient payment for

study involvement as part

of the Symplicity HTN-1

or HTN-2 study), Ministry

of Science and Economy

Funding source: not

relevant. Absence of

conflict of interest.

Funded in part by the

program “Angewandte

klinische Forschung”

(AKF) of the University of

Tübingen.

Absence of any potential

conflict of interest.

Not declared

Author, year, refer-

ence number

Mabin et al. (2012)

Eurointervention.

2012;8:57–61.

Esler et al. (2012)*

Circulation.

2012;126:2976-82

Prochnau et al. (2012a)

Int J Cardiol.

2012;157:447–8.

Simonetti et al. (2012)

Radiol Med

2012;117:426–44.

Country South Africa Europe, Australia, New

Zealand Germany Italy

Declaration of

funding source and

competing inter-

ests

Funded by ReCor Medi-

cal.

One author is member of

the ReCor Medical advi-

sory board. Two authors

are consultants to ReCor

Medical. An author is an

employee of ReCor

Medical.

Funded by Ardian Inc.

Funding source: not

declared. Absence of

conflict of interest.

Funding source: not

declared. Absence of

conflict of interest.

Study design Case series Case series Case series Case series

Study objective

Evaluate the technical

feasibility as well as the

safety and efficacy of a

novel modality for RDN

Report the

6 months outcomes

from cross over patients

from the Symplicity

HTN-2 trial

Evaluate the

efficacy (measured in

the 24-h ambulatory BP

monitoring) and safety

Investigate the efficacy

and safety of

the Ardian Symplicity

catheter system

Intervention RDN and antihyperten-

sion medication

RDN and antihyperten-

sion medication

RDN and antihyperten-

sion medication

RDN and antihyperten-

sion medication

Comparator None Only antihypertension

medication None None

Type of catheter PARADISE™ (ReCor

Medical)

Symplicity®

(Ardian,

Medtronic) (Marinr

®

; Medtronic) Symplicity

®

(Ardian,

Medtronic)

Inclusion/exclusion

criteria

Patients with resistant

hypertension as defined

by the ESH and the ESC,

i.e., with a minimum BP

of 140/90 mmHg (of-

fice), 135/85 mmHg

(home) and 130/80

mmHg (ambulatory)

despite being treated

with at least three anti-

hypertensive drugs

including a diuretic.

Exclusion of patients

under the age of 18

years, vascular abnor-

malities, pregnancy,

allergic to contrast

media, or with any

known cause of second-

ary hypertension

Patients aged 18–85

years with a systolic

BP of 160 mm Hg or

more (≥150 mm Hg in

patients with type 2

diabetes), despite com-

pliance with ≥ 3 antihy-

pertensive drugs

Exclusion of estimated

eGFR < than 45 ml/min

per 1.73 m2

, type 1

diabetes, contraindica-

tions to MRI,substantial

stenotic valvular heart

disease, pregnancy and

a history of myocardial

infarction, unstable

angina, or CVA in the

previous 6 months.

Patients with drug-

resistant hypertension

despite treatment with

at least four antihyper-

tensive drugs (mean 6).

Exclusion of secondary

hypertension.

Essential arterial hyper-

tension not responding

to pharmacological

treatment with ≥ 3

antihypertensive drugs,

including a diuretic; SBP

levels ≥160 mmHg;

normal renal function or

with low or moderate

CRF; age >18 years and

<75 years; absence of

renal pathology or

systemic disease with

possible renal involve-

ment; renal artery length

≥2 cm and minimum

ostial diameter ≥4 mm;

no evidence of accessory

renal arteries; pathologi-

cal microalbuminuria

(>300 mg/24 h); or

altered fundus oculi

examination (varying

degrees of hypertensive

retinopathy) and left

ventricular hypertrophy

at echocardiography.

Exclusion of patients

with secondary causes

of hypertension

Number of patients 11

35*

* 6-month outcomes of

crossover control

patients from Symplici-

ty HTN-2 trial who

were treated with RD

30 5

Age (mean) 55 ± 14 62±14.3 62.4±12.8 50, 6

Sex (M/F) 36% M, 64% F 9 M, 3 F 20 M, 10 F 3 M, 2 F

eGFR (ml/min per

1.73 m2

) - 88.8±20.7 N/A N/A

Follow up 3 months (8 patients) 3 months 12 months 60 days

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of the Federal State of the

Saarland, Deutsche

Hochdruckliga, Deutsche

Forschungsgemeinschaft

(KFO 196) and Deutsche

Gesellschaft für Kardiolo-

gie (DGK).

Differents authors have

received speakers’ hono-

raria from Ardi-

an/Medtronic.

Study

design Case series Case series Case series Case series

Study

objective

Investigate the effects of

RDN on elevated HR and

conduction times

Report the first Danish

experiences and

results with RDN

Test the hypothesis that

RDN leads to a significant

reduction of abnormal BP

variability and instability

Analyse the data in respect of

procedural details, complica-

tions, and radiation

exposure

Interven-

tion

RDN and antihyperten-

sion medication

RDN and antihyperten-

sion medication

RDN and antihyperten-

sion medication

RDN and antihypertension

medication

Compara-

tor None None None None

Type of

catheter

Symplicity®

(Ardian,

Medtronic)

Symplicity®

(Ardian,

Medtronic)

Symplicity®

(Ardian,

Medtronic) Symplicity

®

(Ardian, Medtronic)

Inclusi-

si-

on/exclusi

on criteria

Patients ≥18 years with

resistant hypertension

defined as office systolic

BP of ≥160 mm Hg (≥150

mm Hg for

type 2 diabetics), despite

being treated with ≥ 3

antihypertensive drugs

(including a diuretic),

with no changes in medi-

cation for a minimum of

2 weeks prior to enrol-

ment; not pregnant and

with an eGFFR of ≥45

ml/min/1.73 m2

.

Exclusion of patients with

inadequate renal artery

anatomy, type 1 DM,

myocardial infarction,

unstable angina pectoris,

CVA within the last 6

months, or hemodynami-

cally significant valvular

disease.

Patients with systolic

daytime 24-hour ambula-

tory BP ≥ 135 mmHg

despite being treated

with ≥ 3 antihypertensive

drugs including a diuret-

ic. Exclusion of patients

with confirmed intoler-

ance to medication in

case of pregnancy; age <

18 years; secondary

cause of hypertension;

eGFR rate < 45 ml/min;

LVEF < 50%, recent myo-

cardial infarction or

percutaneous coronary

intervention, significant

proximal coronary artery

stenosis or haemodynam-

ically significant valvular

heart disease.

Patients were > 18 years,

had an office systolic BP

of ≥ 160mmHg

(≥150mmHg for patients

with type2 DM) despite

being treated with at

least three antihyperten-

sive drugs (including one

diuretic), with no changes

in medication for a mini-

mum of 2 weeks before

enrolment. Patients were

included if they were not

pregnant and had an

eGFR ≥ 45ml/min

per

1.73m2

.

Patients with refractory hyper-

tension

Exclusion of patients with

planted pacemakers or cardi-

overter defibrillators

and a vessel diameter below

4mm, assessed in pre-

interventional

Number of

patients

136*

*18 were part of Simplic-

ity HTN2 Study

9 11 53

Age 62.2±0.8 56 ± 10 68.9 59

Sex 79M, 57F 3M, 6F 8M, 3F 35 M, 18 F

eGFR

(ml/min

per 1.73

m2

)

83±3.9 - 75.0 (18.4) 76.4 (Range: 71.5–81.4)

Follow up 6 months 1 month 24 months None

BP: blood pressure; CVA: cardiovascular attack; DM: diabetes mellitus; eGFR: estimated glomerular filtration rate; F: female; HR: heart

rate; M: male; N/A: not available; RDN: renal denervation; mm Hg: Millimeter mercury; min: minute; ml: milliliter; mm: millimeter;

LVEF: left ventricular ejection fraction

Author,

year, refer-

ence num-

ber

Fontenla et al.

(2013)

Rev Esp Cardiol.

2013;66(5):364–70.

Kaltenbach et al.

(2013)

Catheter Cardiovasc

Interv. 2013;81(2):335

-9.

Ormiston et al. (2013)

EuroIntervention

2013;9:70-4.

Worthley et al. (2013)

Eur Heart J. 2013;34(28):2132-40.

Country Spain Germany New Zealand Australia, Greece

Declaration

of funding

source and

competing

interests

Catheters funded by

Fondation pour la

prevention des

maladies cardiovas-

culaires (Geneva,

Switzerland). No

conflict of interest.

Not declared

Funded by Covidien

(Campbell, CA, USA).

The first author is a minor

shareholder in Covidien.

Funded by St. Jude Medical Inc.

Some authors received research

grants and honoraria from St Jude

Medical, Medtronic, Inc., Astra

Zeneca, Eli Lilly, Sanofi Aventis

and Boston Scientific. One author

is a board member from St Jude.

Study de-

sign Case series Case series Case series Case series

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Study ob-

jective

Describe the results

of establishing a

multidisciplinary unit

for the implementa-

tion of renal dener-

vation in the man-

agement of resistant

hypertension

Examine the effects of

renal sympathetic

denervation (feasibility,

safety and effective-

ness)

To provide hypothesis-

generating safety and

feasibility data concerning

the OneShotTM

renal dener-

vation device

Evaluate the safety and efficacy of

a multielectrode RF ablation cathe-

ter

Intervention RDN and antihyper-

tension medication

RDN and antihyperten-

sion medication

RDN and antihypertension

medication

RDN and antihypertension medica-

tion

Comparator None None None None

Type of

catheter

Symplicity®

(Ardian,

Medtronic)

Symplicity®

(Ardian,

Medtronic) OneShot™ (Covidien)

EnligHTN™ Ablation Catheter (St.

Jude Medical)

Inclusion/

exclusion

criteria

Patients with a mean

office systolic BP >

140mmHg or dias-

tolic BP > 40 mmHg

despite being treat-

ed with at least three

antihypertensive

drugs and complying

with the following

criteria: eGFR ≥

45ml/min per

1.73m2

, no history of

coronary or artery

disease in the previ-

ous six months,

coronary artery

stenosis or contrain-

dications for femoral

artery catheterisa-

tion.

Patients with

longstanding mild

hypertension despite

treatment with ≥ 3

antihypertensive drugs.

Exclusion of patients

with definite or pre-

sumed secondary

causes of hypertension

such as renal artery

stenosis, hyperaldoste-

ronism, or pheochro-

mocytoma

Patients ≥ 18 years with

consistent office-measured

systolic BP ≥ 160 mmHg (or

greater than 150 mmHg for

patients with type 2 diabe-

tes) despite treatment with

≥ 2 antihypertensive medi-

cations; renal artery diame-

ters between 4 and 7 mm

and a segment of artery at

least 20 mm in length

devoid of stenosis.

Exclusion of patients with

an eGFR rate < 45

ml/min/1.73 m2

.

Patient ≥18 and ≤80 years old

with office systolic BP that remains

≥160 mmHg (≥150 mmHg for

patient with type 2 diabetes)

despite the stable use of ≥3 anti-

hypertensive medications concur-

rently at maximally tolerated

doses, of which one is a diuretic

or patient that was on diuretic

previously but documented to be

diuretic intolerant, for a minimum

of 14 days prior to enrolment and

with an expectation to maintain

for a minimum of 180 days

Exclusion of patients with renal

artery stenosis, multiple main

renal arteries in either kidney,

main renal arteries are ,4 mm in

diameter or ,20 mm in length, an

eGFR of < 45 ml/min per 1.73m2

,

type 1 DM, identified secondary

cause of hypertension or is in

chronic atrial fibrillation/atrial

flutter

Number of

patients 11 20 9 46

Age 49 ± 13 6 1± 10.8 59.5±15.6 59.9+10.2

Sex 4M, 7F 11M, 9F 5M, 9F 31M, 15F

eGFR

(ml/min per

1.73 m2

)

- 77.4± 24.8 - -

Follow up 6 months

(mean:72 days) 6 months 12 months 6 months

BP: blood pressure; eGFR: estimated glomerular filtration rate; DM: diabetes mellitus F: female; M: male; N/A: not available; RDN:

renal denervation; mm Hg: Millimeter mercury; min: minute; ml: milliliter

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Evidence tables and quality assessment for the ‘clinical effectiveness’ domain

Quality assessment of SRs (3 in total) was done using the English version of the NOKC check-

list for systematic reviews (NOKC SR checklist 2013) adapted from the Cochrane EPOC group

appraisal list for systematic reviews (Grimshaw 2003).

Table 14: Checklist for SR quality assessment

Reference Yes (Y)

Unclear (U)

No (N)

1. Is the specific purpose (question to be answered) stated?

Comment:

2. Are the comparison groups clearly stated?

Comment:

3. Are the sources and search methods used to find evidence (primary studies) on the questions to be answered stated?

Comment:

4. Is the search strategy for evidence reasonably comprehensive?

Comment:

5. Are explicit criteria used for deciding which studies to include in the review?

Comment:

6. Is bias in the selection of articles likely to be avoided?

Comment:

7. Are the reasons for excluding studies from the review reported?

Comment:

8. Are the criteria used for assessing the quality of the studies reported?

Comment:

9. Is the quality of all the studies to be reviewed assessed using appropriate criteria?

Comment:

10. Are the methods used to combine the findings of the relevant studies reported?

Comment:

11. Are the methods used to combine the findings of the relevant studies appropriate to the ques-tions to be answered by the review?

Comment: (1) SBU checklist for appraisal of studies (2) No combined results performed thus not applicable

Overall quality:

Assessed by/date:

Table 15: Evidence tables for SRs

Article Full reference

Andersson B, Herlitz H, Manhem K, Zachrisson K, Völz S, Daxberg EL, et

al. Renal sympathetic denervation in patients with therapy resistant

hypertension: The Regional Health Technology Assessment Centre

(HTA-centrum), Region Vastra Gotaland; 2013.

Project details

Reviewed by KBF and TR

Date of review 10 September 2013

Project name WP5 Strand B 2nd

pilot: Renal denervation systems for treatment-

resistant hypertension

Project ID WP5-SB-12

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Study type

Type of publication Health Technology Assessment

Country (area)

Year

Sweden (Västra Götaland)

2013

Last updated

search August 2012

Research ques-

tion/main

objective

Is RDN an effective and safe technique to lower the BP in patients with treatment-resistant

hypertension, and does it result in reduced mortality and less target organ damage?

Included for Clinical effectiveness

Criteria for

study design

What study design(s) are included by the review:

RCTs

SRs

Studies with some kind of control group

Case series: ≥ 10 patients (for outcome: complications)

No case reports or review articles

Population

Patient characteristics:

Patients with treatment-resistant hypertension (medical treatment with at least three antihy-

pertensive drugs) with BP ≥140/90 mm Hg

Disease/condition:

Treatment-resistant hypertension (medical treatment with at least three antihypertensive

drugs) with BP ≥140/90 mm Hg

Intervention Catheter-based renal denervation

Comparison Conventional pharmacological treatment

Outcomes

Outcomes assessed:

Mortality

Cardiovascular morbidity

Kidney involvement

BP

Complications

Left ventricular hypertrophy/Systolic and diastolic cardiac function (not in our inclusion crite-

ria)

Glucose metabolism (not in our inclusion criteria)

Sources of

information

Systematic searches in PubMed, EMBASE, the Cochrane Library, and a number of HTA-

databases.

Other sources of information:

Reference lists of relevant articles were also scanned for additional references.

Studies includ-

ed for the

different out-

comes

Total: 15 studies included

For the outcomes:

Mortality: none

Cardiovascular morbidity: none

Kidney involvement: one non-randomised controlled study (Mahfoud 2012)

BP: two RCTs (Esler 2010; Ukena 2011) and three non-randomised controlled studies (Brandt

2012b; Mahfoud 2012; Mahfoud 2011b)

Complications (reported only for the intervention groups): four controlled studies (Esler 2010;

Symplicity HTN-1 Investigators 2011; Mahfoud 2012; Mahfoud 2011b) and five case series

(Krum 2009; Mabin 2012; Prouchnau 2012; Voskuil 2011; Zuern 2012)

Left ventricular hypertrophy/Systolic and diastolic cardiac function: one non-randomised con-

trolled study (Brandt 2012b)

Main Conclu-

sion

This catheter-based method, used for patients with therapy-resistant hypertension, signifi-

cantly reduces BP. Even though follow-up data for more than two years are lacking, present

data suggest that the method may be safely used as a treatment alternative in this category of

patients. The present data suggests that the method may be a valuable treatment alternative

in therapy resistant hypertension.

Quality assessment (based on NOKC checklist for systematic reviews)

1 2 3 4 5 6 7 8 9 10 11 Quality

Y Y Y Y Y Y Y Y Y U U HIGH

Comments:

Article Full reference

Davis MI, Filion KB, Zhang D, Eisenberg MJ, Afilalo J, Schiffrin EL, Joyal

D. Effectiveness of renal denervation therapy for resistant hyperten-

sion: a systematic review and meta-analysis. J Am Coll Cardiol. 2013 Jul

16;62(3):231-41.

Project details

Reviewed by KBF and TR

Date of review 10 September 2013

Project name WP5 Strand B 2nd

pilot: Renal denervation systems for treatment-

resistant hypertension

Project ID WP5-SB-12

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Study type

Type of publication Systematic review

Country (area)

Year Canada 2013

Last updated

search December 2012

Research ques-

tion/main

objective

This study sought to determine the current effectiveness and safety of sympathetic renal

denervation (RDN) for resistant hypertension.

Included for Clinical effectiveness

Criteria for

study design

What study design(s) are included by the review:

All study designs (controlled and before-after studies in a single group of patients) with at

least 10 participants with at least 3 months follow-up

Population

Patient characteristics:

Patients with resistant hypertension

Disease/condition:

Resistant hypertension

Intervention Renal denervation therapy (using contemporary percutaneous catheters and radiofrequency

probes)

Comparison Standard medical therapy

Outcomes

Outcomes assessed:

BP

Complications (procedural complications and adverse outcomes including death from any

cause)

Sources of

information

Databases:

PubMed, Embase, Cochrane Library

Other sources of information:

Hand searched references of retrieved articles and use PubMed’s related articles feature

Studies includ-

ed for the

different out-

comes

Totally 12 studies included (Originally 18 studies met all inclusion criteria, but studies were

excluded if there was overlap in patients with another study within the same analysis).

2 RCTs (Esler 2010; Pokushalov 2012)

1 observational study with a control group (Krum 2009)

9 observational studies without a control group (Ahmed 2012; Hering 2012; Kaltenbach 2013;

Mabin 2012; Prochnau 2012a; Symplicity HTN-1 Investigators 2011; Ukena 2012; Witkowski

2011; Zuern 2012)

Mortality: no deaths reported during the stipulated study periods

BP: all 12 studies (meta-analyses performed, separately for controlled and uncontrolled stud-

ies, and for different catheter type)

Procedure safety

Main Conclu-

sion

RDN resulted in a substantial reduction in mean BP at 6 months in patients with resistant

hypertension. The decrease in BP was similar irrespective of study design and type of catheter

employed. Large RCTs with long-term follow-up are needed to confirm the sustained efficacy

and safety of RDN.

Quality assessment (based on NOKC checklist for systematic reviews)

1 2 3 4 5 6 7 8 9 10 11 Quality

Y Y Y Y Y U Y Y Y Y Y HIGH

Comments:

Article Full reference

Gosain P, Garimella PS, Hart PD, Agarwal R. Renal Sympathetic Denerva-

tion for Treatment of Resistant Hypertension: A Systematic Review. J

Clin Hypertens 2013;15(1):75-84.

Project details

Reviewed by KBF and TR

Date of review 10 September 2013

Project name WP5 Strand B 2nd

pilot: Renal denervation systems for treatment-

resistant hypertension

Project ID WP5-SB-12

Study type

Type of publication Systematic review

Country (area)

Year

USA

2013

Last updated

search June 2012

Research ques-

tion/main

objective

Systematically evaluate the existing literature on the safety and efficacy of renal sympathetic

denervation in persons with resistant hypertension

Included for Clinical effectiveness

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Criteria for

study design

What study design(s) are included by the review:

RCTs

Observational studies

Case series

Conference presentations

Studies with <5 patients were excluded.

Population

Patient characteristics:

Not clearly pre-defined in any inclusion criteria

Resistant hypertension is defined as the failure to achieve a goal BP in persons adhering to full

doses of a 3-drug antihypertensive regimen that includes a diuretic

Disease/condition:

-Resistant hypertension

Intervention Not clearly pre-defined in any inclusion criteria

Catheterbased endovascular renal artery sympathetic denervation

Comparison Not clearly pre-defined in any inclusion criteria

Outcomes

Outcomes assessed:

BP

Complications (adverse events)

Kidney function

Decrease in number of medications (may affect activities of daily living, question D0016)

Sources of

information

Databases:

Medline; Cochrane Library

Other sources of information:

The American College of Cardiology, the American Society of Nephrology, and Google Scholar

databases were also searched for conference proceedings and presentations.

Studies includ-

ed for the

different out-

comes

Total: 19 studies included

2 RCTs (Ukena 2011; Esler 2010)

4 case-control studies (Mahfoud 2011b, Mahfoud 2012; Brandt 2012b; Krum 2012)

13 case series (Bauer 2012; Hering 2012; Himmel 2012; Mabin 2012; Mylotte 2012; Prochnau

2012a; Prochnau 2012b; Vase 2012; Verloop 2012; Simonetti 2011; Voskuil 2011; Witkowsky

2011)

BP (change in BP, home-based BP measurement and ABPM, maintainance of BP reduction at 12

months) (2 RCTs (Ukena 2011; Esler 2010) and 4 case-control studies (Mahfoud 2012; Brandt

2012b; Mahfoud 2011b; Krum 2009) and in 8 case series (Hering 2012; Himmel 2012;Mabin

2012;Mylotte 2012; Verloop 2012; Symplicity HTN-1 2011; Voskuil 2011; Witkowsky 2011)

Decrease in number of medications reported as narrative summary, reference to 11 studies.

Change in renal function: 2 RCTs (Ukena 2011; Esler 2010) and 4 case-control studies (Mah-

foud 2012; Brandt 2012b; Mahfoud 2011b; Krum 2009) and in 8 case series (Hering 2012;

Prochnau 2012a; Prochnau 2012b; Vase 2012; Symplicity HTN-1 2011; Simonetti 2011;

Voskuil 2011; Witkowsky 2011)

Adverse events:

-periprocedural adverse events (for pseudoaneurysm: Ukena 2011; Mahfoud 2011b; Brandt

2012b; Symplicity HTN-1 Investigators 2011 and for renal artery dissection: Brandt 2012b;

Symplicity HTN-1 Investigators 2011)

-back and/or flank pain (Mahfoud 2011b; Mabin 2012, Symplicity HTN-1 Investigators 2011)

-intraprocedural bradycardia requiring atropine (Ukena 2011)

-no changes in renal artery anatomy or development of clinical significant stenosis on follow-

up CT-angiography and MR imaging studies (? Studies)

Main Conclu-

sion

Our review suggests that renal sympathetic denervation has a role in the management of

carefully selected patients with resistant hypertension. Currently ongoing and future research

will provide further evidence about the efficacy and safety and should clarify unanswered

questions about patient selection and the intervention itself.

Quality assessment (based on NOKC checklist for systematic reviews)

1 2 3 4 5 6 7 8 9 10 11 Quality

Y U Y Y Y Y Y N U U U HIGH

Comments:

Table 16: Evidence tables for controlled trials

Article

Ahmed H, Neuzil P, Schejbalova M, Bejr M, Kralovec S, Reddy VY. Renal sympathetic denerva-

tion for the management of chronic hypertension (Relief): 40 patient analysis. Circulation

2012;Conference(var.pagings)

Volume 126(21) Supplement, 20 November 2012. Abstracts From the American Heart Associ-

ation 2012 Scientific Sessions and Resuscitation Science Symposium

Project details

Reviewed by TR and KBF

Date of review 19 September 2013

Project name

WP5 Strand B 2nd

pilot: Renal denervation systems for treatment-

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resistant hypertension

Project ID WP5-SB-12

Study type Prospective, randomised, single-blinded controlled trial

Study objective

Considered whether renal sympathetic denervation (RSDN) could be achieved using an off-the-

shelf saline-irrigated radiofrequency ablation (RFA) catheter typically employed for cardiac

tissue ablation.

Included for

domain(s) Clinical effectiveness

Study inclu-

sion/

exclusion cri-

teria

Patients with hypertension refractory to ≥3 anti-hypertensive drugs, including one diuretic

No. partici-

pants

Total: 40

Intervention: 19

Control: 21

Population

Baseline characteristics Intervention Control

Age (years, mean+/-SD) Not reported Not reported

Sex Not reported Not reported

Resting BP (mm Hg, mean+/-SD) Not reported Not reported

eGFR (ml/min/1,73 m2

, mean+/-SD) Not reported Not reported

No. hypertensive drugs (mean+/-SD) Not reported Not reported

Intervention Bilateral RSDN with a saline-irrigated RFA catheter

Comparison Sham procedure (manipulation of catheter within the renal arteries without the delivery of any

energy)

Co-

intervention

description

Not reported

Follow-up 3 months (Measurements at baseline and at 3 mo.)

Outcomes

Ambulatory BP recordings (24-hour)

Article

Mahfoud et al.: Renal denervation reduces left ventricular mass in patients with resistant hyper-

tension - results from a multicenter CMR-study. Journal of Cardiovascular Magnetic Resonance

2013b 15(Suppl 1):E108.

(doi:10.1186/1532-429X-15-S1-E108)

Project de-

tails

Reviewed by TR and KBF

Date of review 20 September 2013

Project name WP5 Strand B 2nd

pilot: Renal denervation systems for treatment-

resistant hypertension

Project ID WP5-SB-12

Study type Controlled trial (non-randomised)

Study objec-

tive

To investigate the effect of RD on left ventricular mass, assessed by cardiac magnetic resonance

(CMR), in patients with resistant hypertension compared to a control group of medical treated

patients.

Included for

domain(s) Clinical effectiveness

Study inclu-

sion/

exclusion

criteria

Patients with resistant hypertension (defined as office systolic BP >160 mmHg and >150 mmHg

for patients with type 2 diabetes)

No. partici-

pants

Total: 46

Intervention:37

Control: 9

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Population

Baseline characteristics Intervention Control

Age (years, mean+/-SD) 63 ± 11 70 ± 8

Sex Not reported Not reported

Resting BP (mm Hg, mean+/-SD) Not reported Not reported

eGFR (ml/min/1,73 m2

, mean+/-SD) Not reported Not reported

No. hypertensive drugs (mean+/-SD) Not reported Not reported

Reported as poorly controlled BP and heavily medicated

Intervention Catheter-based renal denervation (RD)

Comparison Medical treated patients.

Co-

intervention

description

None

Follow-up 6 months

Outcomes

left ventricular mass, assessed by cardiac magnetic resonance (CMR)

Ejection fraction

End systolic volume / end diastolic volume

Pokushalov was included in the SR by Davis 2013. It was described and assessed for risk

of bias therein.

Article

Ukena C, Mahfoud F, Kindermann I, Barth C, Lenski M, Kindermann M, et al. Cardiorespiratory

response to exercise after renal sympathetic denervation in patients with resistant hypertension.

J Am Coll Cardiol 2011;58(11):1176-82.

Project de-

tails

Reviewed by TR and KBF

Date of review 19 September 2013

Project name WP5 Strand B 2nd

pilot: Renal denervation systems for treatment-

resistant hypertension

Project ID WP5-SB-12

Study type RCT. Multicentre, single country (Germany)

Study objec-

tive

To investigate the effects of interventional renal sympathetic denervation (RD) on cardiorespira-

tory response to exercise.

Included for

domain(s) Clinical effectiveness

Study inclu-

sion/

exclusion

criteria

Resistant hypertension BP≥160 mm Hg (≥150 for type 2 diabetics) despite use of ≥3 antihyper-

tensive drugs (including a diuretic).

Exclusion criteria include: estimated glomerular filtration rate (eGFR; based on the Modification

of Diet in Renal Disease criteria12) of less than 45 mL/min per 1.73 m2

, type 1 diabetes, contra-

indications to MRI, substantial stenotic valvular heart disease, pregnancy or planned pregnancy

during the study, and a history of myocardial infarction, unstable angina, or cerebrovascular

accident in the previous 6 months.

No. partici-

pants

Total: 46

Intervention: 37

Control: 9

Population

Baseline characteristics Intervention Control

Age (years, mean+/-SD) 59,1+/-9,4 64,9+/-6,4

Sex Male 25 (68 %) Male 7 (79 %)

Resting BP (mm Hg, mean+/-SD) SBP 172+/-24

DBP 94+/-19

SBP 166+/-23

DBP 90+/-7

eGFR (ml/min/1,73 m2

, mean+/-SD) 70+/-24 64,5+/-16

No. hypertensive drugs (mean+/-SD) 5,9+/-1,4 5,0+/-1,2

Intervention

The femoral artery was accessed with the standard endovascular technique and the Symplicity

catheter was advanced into the renal artery and connected to a radiofrequency generator. Four-

to-six discrete, low-power radio frequency treatments were applied along the length of both

main renal arteries.

Comparison Standard pharmaceutical treatment

Co-

intervention

description

Changes to baseline doses of all anti-hypertensive drugs were not allowed, unless judged medi-

cally necessary because of changes in BP in association with signs or symptoms.

Follow-up 3 months (Measurements at baseline and at 3 mo.)

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Outcomes

Cardiopulmonary exercise testing: breath-by-breath gas exchange analyses. Exercise on

reclining ergometer, work rate increased continuously by 15 W/min. ECG continuously, BP

measured every 2 min. manually by experienced physician.

Maximum achieved work rate

Peak oxygen consumption

Oxygen uptake at the anaerobic threshold (AT)

VE/VCO2

Heart rate recovery: reduction in heart rate from peak exercise to the heart rate 1 min after

the cessation of exercise

Risk of bias tables

Risk of bias tables for the ‘safety’ domain

Quality of bias was assessed using the Cochrane risk of bias checklist for RCTs (Higgins

2011), selecting the specific criteria relevant for each design.

Table 17: Risk of bias tables of included RCTs (3 in total)

Entry (Symplicity HTN-2 2010) Judgment Support for judgment

Random sequence generation (selec-

tion bias) Low risk of bias

Patients randomly assigned to intervention or control

group using a sealed envelope (1:1)

Allocation concealment (selection

bias) Low risk of bias Patients randomly assigned using a sealed envelope

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Not reported. Unclear as to how this could influence com-

pliance with pharmacological medication and thus have

an effect on safety aspects (for example, hypotensive and

hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

unclear if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias Three losses in each group.

Selective reporting (reporting bias) Unclear risk of

bias

Not all of the pre-specified safety outcomes have been

reported in a pre-specified way.

Other biases Unclear risk of

bias Funded by Ardian Inc.

Entry (Ukena 2011) Judgment Support for judgment

Random sequence generation (selec-

tion bias)

Unclear risk of

bias

Random assignment of patients to control and RD group

in a 1 to 3 ratio (9 control, 37 RD).

However, this study included 28 patients included in the

Simplicity HTN-2 trial but extended with an extra 18 pa-

tients with the same inclusion and exclusion criteria. The

HTN-2 trial used 1:2 ratio and how this was converted to a

1:3 ratio is not described

Allocation concealment (selection

bias)

High risk of

bias

Not reported. Unclear if allocation was properly concealed

as this study included patients from one study extended

by additional patients.

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants knew treatment allocation. Unclear as to how

this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

unclear if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias Complete outcome data acquired

Selective reporting (reporting bias) High risk of

bias

Safety outcomes are reported incompletely. Authors only

report that RDN was performed without serious adverse

events in all patients. Definitions of what is considered a

serious adverse event are not provided and post-

procedural adverse events are not reported.

Other biases Unclear risk of All authors have worked at centers receiving per-patient

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bias payment for study involvement as part of the Simplicity

HTN-1 and HTN-2 study.

Entry (Pokushalov 2012) Judgment Support for judgment

Random sequence generation (selec-

tion bias) Low risk of bias

Patients randomly assigned to intervention or control

group using a coded envelope system (14:13)

Allocation concealment (selection

bias) Low risk of bias

Patients randomly assigned to intervention or control

group using a coded envelope system

Blinding of participants and person-

nel (performance bias) Low risk of bias Described as a prospective doble-blind randomised study.

Blinding of outcome assessment

(detection bias) Low risk of bias Described as a prospective doble-blind randomised study.

Incomplete outcome data addressed

(attrition bias) Low risk of bias No incomplete data.

Selective reporting (reporting bias) High risk of

bias

Safety outcomes are not pre-specified and adverse events

are reported incompletely. Authors only report that no

procedure related complications or stenosis ocurred.

Other biases Unclear risk of

bias

Two authors have served as consultants with Medtronic

and Biosense Webster. One author has received research

grnas from Medtronic and Biosense Webster and another

works for Ardian Inc.

Table 18: Risk of bias tables of included non-RCTs (3 in total)

Entry (Mahfoud et al 2012) Judgment Support for judgment

Random sequence generation (selec-

tion bias) N/A

Allocation concealment (selection

bias)

Unclear risk of

bias

It is unclear how patients were allocated. It indicates that

88 patients were prospectively assigned to intervention

group following protocols of ongoing trials and 12 to the

control group. It states that patients were matched in

terms of baseline characteristics. 19 patients were includ-

ed in HTN-1 or HTN-2 trial.

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants knew treatment allocation. Unclear as to how

this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments..

Incomplete outcome data addressed

(attrition bias) Low risk of bias No incomplete data

Selective reporting (reporting bias) High risk of

bias

Safety outcomes are not pre-specified. Authors report that

the procedure was performed without any complication in

97% of the patients and that no significant post-

procedural artery stenosis or aneurysms were detected,

Other post-procedural complications are not accounted

for.

Other biases Unclear risk of

bias

Funded by Ardian Inc. An author is an employee of Ardian

Inc. And another is supported by a Senior Research Fel-

lowship.

Entry (Mahfoud et al 2011b) Judgment Support for judgment

Random sequence generation (selec-

tion bias) N/A

Allocation concealment (selection

bias)

Unclear risk of

bias

Includes 37 intervention and 13 controls, uncertainty as

to how patients were allocated (17 interventions and 9

controls included in the HTN-2 trial). Patients were

matched in terms of baseline characteristics

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants knew treatment allocation. Unclear as to how

this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias No incomplete data

Selective reporting (reporting bias) High risk of

bias

Safety outcomes are not pre-specified and adverse events

are incompletely documented. Authors only report that

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one treated patient developed a pseudoaneurysm and

state that no other complications were observed. Authors

do not document on post-procedural complications in

neither group,

Other biases Unclear risk of

bias

Funded by Ardian Inc. An author is an employee of Ardian

Inc. And another is supported by a Senior Research Fel-

lowship.

Entry (Brandt et al 2012a) Judgment Support for judgment

Random sequence generation (selec-

tion bias) N/A

Allocation concealment (selection

bias)

Unclear risk of

bias

Includes 46 interventions and 18 controls. Uncertainty as

to how patients were allocated. It establishes that patient

demographic and clinical characteristics did not differ

between the RD and control groups

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants knew treatment allocation. Unclear as to how

this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias) Low risk of bias

Analysers masked to treatment assignment and sequence

of images. It is uncertain if this can influence antihyper-

tension treatment adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias No incomplete data

Selective reporting (reporting bias) High risk of

bias

Safety outcomes are not pre-specified and and adverse

events incompletely documented.

Other biases Unclear risk of

bias

Funded by Ardian Inc. An author is a conslultan of Ardian

Inc. and another has received a grant support.

Table 19: Risk of bias tables of observational studies (16 in total)

Entry (Symplicity HTN-1) Judgment Support for judgment

Selection bias Unclear risk of

bias

Does not report if it includes all patients that comply with

preselection criteria (consecutive patients).

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not blinded to treatment. It states that

clinicians were encouraged not to change medication

unless absolutely necessary and this was more strictly

applied in the first year. It is uncertain if this could affect

prescription and alter long term safety results.

Incomplete outcome data addressed

(attrition bias)

Unclear risk of

bias

81/92 patients have 6 months follow up data. It docu-

ments that the first 20 patients were assessed via angi-

ography and the following patients by RMN, CT or duplex

scan.

Selective reporting (reporting bias) Low risk of bias

Safety outcomes are not pre-specified. Results given on

periprocedural safety, renal vascular safety, renal func-

tion, postural hypotension and edema and pain.

Other biases Unclear risk of

bias

Funded by Ardian Inc. Three authors are employees of

Ardian Inc.

Entry (Voskuil et al 2011) Judgment Support for judgment

Selection bias) Unclear risk of

bias

Does not report if it includes all patients that comply with

preselection criteria (consecutive patients)

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias)

Unclear risk of

bias

81/92 patients have 6 months follow up data. It docu-

ments that intravascular ultrasound was carried out in 3

patients.

Selective reporting (reporting bias) High risk of

bias

Safety outcomes are not pre-specified and complications

incompletely documented. Authors report that no patients

showed endovascular damage at final angiography and

that in the small subgroup IVUS was performed (n=3) no

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dissections or other intravascular complications were

reported,

Other biases Unclear risk of

bias Conflict of interests not declared.

Entry (Brinkmann et al 2012) Judgment Support for judgment

Selection bias Unclear risk of

bias

Authors state that they included non pre-selected patients

but give no further information.

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias No incomplete data

Selective reporting (reporting bias) High risk of

bias

Safety outcomes are not pre-specified and adverse events

are incompletely documented. Authors only report that

they encountered no procedure related serious adverse

events.

Other biases Low risk of bias Absence of conflict of interest.

Entry (Hering et al 2012) Judgment Support for judgment

Selection bias Unclear risk of

bias

Does not report if it includes all patients that comply with

preselection criteria (consecutive patients)

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias

Follow up data for all patients (n=11) at 3 months and 8

patients at 6 months.

Selective reporting (reporting bias) Unclear risk of

bias

Safety outcomes are not pre-specified. Authors declare

that there were no peri or post procedural complications

and no compromise of treated arteries.

Other biases Unclear risk of

bias

Several investigators have received honoraria from Med-

tronic. Two authors serving on scientific advisory board

and one author employed by Ardian Inc.

Entry (Mabin et al 2012) Judgment Support for judgment

Selection bias Low risk of bias Consecutive patients included.

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias

Follow-up measurements were available for all patients at

two weeks and one month, and 8/11 patients at two and

three months.

Selective reporting (reporting bias) High risk of

bias

Safety outcomes are not pre-specified and adverse events

inadequately recorded. Authors document that they were

no serious complications at the puncture site and yet they

report one renal artery dissection. They state that there

were no device related serious complications with the

exception of the worsening of a headache condition.

Other biases Unclear risk of

bias

Funded by ReCor Medical. One author is a member of the

advisory board, two are consultants and one is an em-

ployee of ReCor Medical.

Entry (Esler et al 2012) Judgment Support for judgment

Selection bias High risk of

bias

Uncertainty regarding patient selection. Study provides

results for 46 control patients from the HTN-2 trial that

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decided to cross over to RDN (9 excluded).

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias Follow up data for 35/37 included patients.

Selective reporting (reporting bias) High risk of

bias

Safety outcomes are not pre-specified and complications

inadequately reported. Authors only make reference to

complications that require hospitalization.

Other biases Unclear risk of

bias Funded by Ardian Inc.

Entry (Prochnau et al 2012a) Judgment Support for judgment

Selection bias Unclear risk of

bias

Does not report if it includes all patients that comply with

preselection criteria (consecutive patients)

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias No losses reported

Selective reporting (reporting bias) High risk of

bias

Safety outcomes are not pre-specified and adverse events

inadequately documented. Authors only report that there

were no renal artery stenosis or .other abnormalities in all

patients

Other biases Low risk of bias Absence of conflict of interest

Entry (Simonetti et al 2012) Judgment Support for judgment

Selection bias Unclear risk of

bias

Does not report if it includes all patients that comply with

preselection criteria (consecutive patients)

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias No incomplete data

Selective reporting (reporting bias) Unclear risk of

bias

Safety outcomes are not pre-specified. Authors document

that no complications occurred either intra- or periproce-

durally or at the 30- and 60-day follow-up

Other biases Unclear risk of

bias Absence of conflict of interest

Entry (Ukena et al 2012) Judgment Support for judgment

Selection bias Unclear risk of

bias

Does not report if it includes all patients that comply with

preselection criteria (consecutive patients)

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias) Low risk of bias Analysers blinded to treatment.

Incomplete outcome data addressed

(attrition bias)

Unclear risk of

bias

127/136 patients presented at 3-month follow-up and 88

patients at 6-month follow-up (6 M).

Selective reporting (reporting bias) High risk of

bias

Safety outcomes are not pre-specified. Authors document

that no serious complications occurred.

Other biases Unclear risk of

bias

Funded by Ardian. All authors have received payment for

study involvement.

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Entry (Vase et al 2012) Judgment Support for judgment

Selection bias Unclear risk of

bias

Does not report if it includes all patients that comply with

preselection criteria (consecutive patients)

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias No incomplete data.

Selective reporting (reporting bias) Unclear risk of

bias

Safety outcomes are not pre-specified. Authors document

that no complications occurred during or after the proce-

dure.

Other biases Low risk of bias Absence of conflict of interest

Entry (Zuern et al 2012) Judgment Support for judgment

Selection bias Low risk of bias Consecutive patients included

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias No incomplete data.

Selective reporting (reporting bias) Unclear risk of

bias

Safety outcomes are not pre-specified. Authors document

that procedure was performed without periprocedural

complications.

Other biases Low risk of bias Absence of conflict of interest.

Entry (Scheurig-Muenker et al

2012) Judgment Support for judgment

Selection bias Low risk of bias Consecutive patients included

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias No incomplete data.

Selective reporting (reporting bias) Low risk of bias Safety outcomes are not pre-specified but complications

adequately described.

Other biases Unclear risk of

bias Conflict of interests not declared.

Entry (Fontela et al 2013) Judgment Support for judgment

Selection bias Unclear risk of

bias

Does not report if it includes all patients that comply with

preselection criteria (consecutive patients)

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias No incomplete data.

Selective reporting (reporting bias) Unclear risk of

bias

Safety outcomes are not pre-specified. Authors document

that procedure was performed without incidents.

Other biases Low risk of bias Absence of conflict of interest.

Entry (Kaltenbach et al 2013) Judgment Support for judgment

Selection bias Unclear risk of

bias

Does not report if it includes all patients that comply with

preselection criteria (consecutive patients)

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Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias No incomplete data.

Selective reporting (reporting bias) Unclear risk of

bias

Study only contemplates procedural safety defined as

freedom from renal abnormalities. Authors make refer-

ence to no serious adverse events related to the proce-

dure or device.

Other biases Unclear risk of

bias Not declared.

Entry (Ormiston et al 2013) Judgment Support for judgment

Selection bias Unclear risk of

bias

Does not report if it includes all patients that comply with

preselection criteria (consecutive patients)

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias No incomplete data.

Selective reporting (reporting bias) Low risk of bias Safety endpoints clearly pre-specified

Other biases Hig risk of bias Funded by Covidien. Some authors received grants and

one author is a board member of St Jude.

Entry (Worthley et al 2013) Judgment Support for judgment

Selection bias Unclear risk of

bias

Does not report if it includes all patients that comply with

preselection criteria (consecutive patients)

Blinding of participants and person-

nel (performance bias)

Unclear risk of

bias

Participants were not blinded to treatment. Unclear as to

how this could influence compliance with pharmacological

medication and thus have an effect on safety aspects (for

example, hypotensive and hypertensive crisis).

Blinding of outcome assessment

(detection bias)

Unclear risk of

bias

Analysers were not masked to treatment assignment. It is

uncertain if this can influence antihypertension treatment

adjustments or safety assessments.

Incomplete outcome data addressed

(attrition bias) Low risk of bias No incomplete data.

Selective reporting (reporting bias) Low risk of bias Study provides a complete list of serious and non serious

adverse events

Other biases Unclear risk of

bias Not declared

Risk of bias tables for the ‘clinical effectiveness’ domain

Quality of the controlled trials (4 in total) was assessed using the Cochrane risk of bias

checklist for RCTs (Higgins 2011).

Table 20: Risk of bias tables of included controlled trials (3 in total)

Entry (Ahmed 2012) Judgment Support for judgment

Random sequence generation (selec-

tion bias)

Unclear risk of

bias

Not reported, other than “prospective, randomised, sin-

gle-blinded trial”

Allocation concealment (selection

bias)

Unclear risk of

bias

Not reported, other than “prospective, randomised, sin-

gle-blinded trial”

Blinding of participants and person-

nel (performance bias) Low risk of bias Participants blinded (reported as single-blinded trial)

Blinding of outcome assessment

(detection bias) Low risk of bias

Ambulatory BP recordings (24-hour) unlikely to be affect-

ed

Incomplete outcome data addressed

(attrition bias) Low risk of bias Complete outcome data acquired

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Selective reporting (reporting bias) Low risk of bias None detected

Other biases Unclear risk of

bias

Author Disclosures: H. Ahmed: None. P. Neuzil: None. M.

Schejbalova: None. M. Bejr: None. S. Kralovec: None. V.Y.

Reddy: Consultant/Advisory Board; Modest; Medtronic,

Philips, Cardioinsight. Research Grant; Significant; Bio-

sense-Webster, Medtronic, St Jude Medical, Boston-

Scientific, Cardiofocus, Voyage Medical, Philips, ACT,

Endosense, Vytronus. Consultant/Advisory Board; Signifi-

cant; Biosense-Webster, St Jude Medical, Boston Scientific,

Cardiofocus, Voyage Medical, ACT, Endosense, Vytronus

Entry (Mahfoud 2013b) Judgment Support for judgment

Random sequence generation (selec-

tion bias)

High risk of

bias

Randomisation not described or not performed.

“CMR was performed in 37 patients at baseline and 6

months after RD in a multicenter setting with 9 subjects

serving as controls.”

Allocation concealment (selection

bias)

Unclear risk of

bias

It is described as a mulitcenter study, but allocation is not

described.

Blinding of participants and person-

nel (performance bias) Low risk of bias

Lack of blinding unlikely to affect the outcomes LV mass

and ejection fraction

Blinding of outcome assessment

(detection bias) Low risk of bias

“Clinical data and CMR results were analyzed blinded at

both times.”

Incomplete outcome data addressed

(attrition bias)

High risk of

bias

Patient flow not reported, neither how many that are

included in the analyses and results

Selective reporting (reporting bias) Unclear risk of

bias

Seems like not all data are presented. Data reported as

before-after within each group and not across groups.

Other biases Unclear risk of

bias Funding by Medtronic.

Pokushalov was included in the SR by Davis 2013. It was described and assessed for risk of

bias therein.

Entry (Ukena 2011) Judgment Support for judgment

Random sequence generation (selec-

tion bias)

Unclear risk of

bias

Random assignment of patients to control and RD group

in a 1 to 3 ratio (9 control, 37 RD).

However, this study included 28 patients included in the

Simplicity HTN-2 trial but extended with an extra 18 pa-

tients with the same inclusion and exclusion criteria. The

HTN-2 trial used 1:2 ratio and how this was converted to a

1:3 ratio is not described

Allocation concealment (selection

bias)

High risk of

bias

Not reported.

Hence, unclear if allocation was properly concealed as this

study included patients from one study extended by addi-

tional patients.

Blinding of participants and person-

nel (performance bias) Low risk of bias

Participants knew treatment allocation. Unclear if that

would influence their exercise effort.

“The physician supervising the exercise testing was blind-

ed to the randomization”

Blinding of outcome assessment

(detection bias) Low risk of bias

“experienced physician used manual sphygmomanome-

ter”. Other assessments based on automated equipment.

Incomplete outcome data addressed

(attrition bias) Low risk of bias Complete outcome data acquired

Selective reporting (reporting bias) Low risk of bias None detected

Other biases Unclear risk of

bias

All authors have worked at centers receiving per-patient

payment for study involvement as part of the Simplicity

HTN-1 and HTN-2 study.

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GRADE profiles for the different outcomes

The classification and definitions of the quality of the evidence include: high (i.e. “We are

very confident that the true effect lies close to that of the estimate of effect”), moderate (i.e.

“We are moderately confident in the effect estimate: the true effect is likely to be close to the

estimate of effect, but there is a possibility that it is substantially different”), low (i.e. “Our

confidence in the effect estimate is limited: the true effect may be substantially different

from the estimate of the effect”) and very low (i.e. “We have very little confidence in the effect

estimate: the true effect is likely to be substantially different from the estimate of effect”).

GRADE profiles for ‘safety’ domain

Table 21: GRADE profiles for ’safety’

Nº of

studies /

patients

Design Risk of bias Inconsistency Indirectness Other consider-

ations Effect size (%)

Quality of

evidence Importance

Outcome: total adverse events (in % of patients)

3/228 RCTs no serious

risk of bias

no serious

inconsistency serious

1,2

none 0-40.38 vs.0-9.26

LOW CRITICAL

3/260

Open, non

randomised,

controlled

no serious

risk of bias

no serious

inconsistency

no serious

indirectness none 0-23.9 vs. 0

LOW CRITICAL

18/599 Observational

studies

no serious

risk of bias

no serious

inconsistency

no serious

indirectness none 0-100

VERY LOW CRITICAL

Outcome: major adverse events (in % of patients)

4/274 RCTs no serious

risk of bias

no serious

inconsistency serious

1,2

none 0-15.38 vs. 0-9.26

LOW CRITICAL

3/260

Open, non

randomised,

controlled

no serious

risk of bias

no serious

inconsistency

no serious

indirectness none 0 vs. 0

LOW CRITICAL

18/599 Observational

studies

no serious

risk of bias

no serious

inconsistency

no serious

indirectness none 0-33.33

VERY LOW CRITICAL

1

Tested pulmonary vein isolation +/- renal denervation. Participants had atrial fibrillation in addition to treatment

resistant hypertension.

2

Combination of different catheter types. Uncertain transferability.

GRADE profiles for ‘clinical effectiveness’ domain

Table 22a: GRADE profiles for ’clinical effectiveness’– mortality and cardiovascular morbidity

Quality assessment No

of patients Effect

Quality Importance

No

of

studies Design Risk of bias Inconsistency Indirectness Imprecision

Other consid-

erations

Renal

denervation Control

Relative

(95% CI) Absolute

Overall mortality

Assessed narratively as No change (Davis 2013) CRITICAL

Cardiovascular mortality

This was not assessed in any of the included SRs and controlled trials CRITICAL

Stroke, heart failure, heart disease

No evidence available CRITICAL

LV mass (hypertrophy) - Symplicity®

- LV mass post treatment at 6 months (measured with: LV mass/body surface area (g/m2); Better indicated by

lower values)

1 non-

RCT

no serious

risk of bias2

no serious

inconsistency

no serious

indirectness

very

serious1,3

none 46 18 -

MD 23.8 lower

(40.16 to 7.44

lower)

VERY

LOW

IMPORTANT

LV hypertrophy - Symplicity®

- LV mass post treatment at 6 months (measured with: LV mass indexed to height 1.7 (g/m1.7); better indicated by

lower values)

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1 non-

RCT

no serious

risk of bias2

no serious

inconsistency

no serious

indirectness

very

serious1,3

none 37 9 -

MD 3.6 higher

(3.57 lower to

10.77 higher)

VERY

LOW

IMPORTANT

LV hypertrophy – Navistar ThermoCool®

- LV mass change at 6 months (measured with: LVMI (g/m); better indicated by lower values)

1 RCT no serious

risk of bias

no serious

inconsistency serious

4

very

serious1,3

none 13 14 -

MD 15.4 lower

(20.05 to 10.75

lower)

VERY

LOW

IMPORTANT

1

Few participants (GRADE give suggested recommendation for imprecision: total population size is less than 400 (a threshold rule-of-thumb value; using

the usual I± and I², and an effect size of 0.2 standard deviation (SD), representing a small effect)

2

Controlled but not randomised trial.

3

Only one study, unknown reproducibility

4

Tested pulmonary vein isolation +/- renal denervation. Participants had atrial fibrillation in addition to treatment-resistant hypertension.

LV: left ventricular

Table 22b: GRADE profiles for ‘clinical effectiveness’ – BP

Quality assessment No

of patients Effect

Quality Importance

No

of

studies Design

Risk

of bias Inconsistency Indirectness Imprecision

Other

consider-

ations

Renal

denervation Control

Relative

(95%

CI)

Absolute

Change in systolic BP at 6 months (follow-up 6 months; measured with: Office based (mm Hg); Better indicated by lower values)

3 RCTs

no

serious

risk of

bias1

no serious

inconsistency serious

2,3

serious4

none 88 70 -

MD 29.80 lower

(37.2 to 20.6

lower)

LOW CRITICAL

Symplicity®

- Change in SBP at 6 months (measured with: Office-based (mm Hg); Better indicated by lower values)

2 RCTs

no

serious

risk of

bias1

no serious

inconsistency

no serious

indirectness serious

4

none 75 56 -

MD 33.6 lower

(41.33 to 25.88

lower)

MODERATE CRITICAL

Navistar - Change in SBP at 6 months (measured with: Office based (mm Hg); Better indicated by lower values)

1 RCT

no

serious

risk of

bias

no serious

inconsistency serious

2

very

serious4,5

none 13 14 -

MD 23 lower (29.2

to 16.8 lower)

VERY LOW CRITICAL

Change in DBP at 6 months (follow-up 6 months; measured with: Office based (mm Hg); Better indicated by lower values)

3 RCTs

no

serious

risk of

bias1

no serious

inconsistency serious

2,3

serious4

none 88 70 -

MD 11.04 lower

(16.41 to 5.68

lower)

LOW CRITICAL

Symplicity®

- Change in DBP at 6 months (measured with: Office-based (mm Hg); Better indicated by lower values)

2 RCTs

no

serious

risk of

bias1

no serious

inconsistency

no serious

indirectness serious

4

none 75 56 -

MD 13.76 lower

(20.25 to 7.27

lower)

MODERATE CRITICAL

Navistar - Change in DBP at 6 months (measured with: Office based (mm Hg); Better indicated by lower values)

1 RCT

no

serious

risk of

bias

no serious

inconsistency serious

2

very

serious4,5

none 13 14 -

MD 7 lower (11.53

to 2.47 lower)

VERY LOW CRITICAL

1

Mix of randomised and non-randomised CT (Combined as in the SR).

2

Tested pulmonary vein isolation +/- renal denervation. Participants had atrial fibrillation in addition to treatment-resistant hypertension.

3

Combination of different catheter types. Uncertain transferability.

4

Few participants (GRADE give suggested recommendation for imprecision : total population size is less than 400 (a threshold rule-of-thumb value; using

the usual α and β, and an effect size of 0.2 SD, representing a small effect).

5

Only one study, unknown reproducibility

Mm Hg: millimeter mercury; MD: Mean difference

Table 22c: GRADE profiles for ‘clinical effectiveness’ – body function

Quality assessment No

of patients Effect

Quality Importance

No

of

studies Design

Risk of

bias Inconsistency Indirectness Imprecision

Other

consider-

ations

Renal dener-

vation Control

Relative

(95%

CI)

Absolute

Change in eGFR at 6 months - RCT (measured with: lab analysis; Better indicated by lower values)

1 RCT

no

serious

risk of

bias

no serious

inconsistency

no serious

indirectness

very

serious1,2

none 49 51 -

MD 0.7 lower

(5.21 lower to

3.81 higher)

LOW IMPORTANT

Change in creatinine at 6 months - RCT (measured with: lab analysis; Better indicated by lower values)

1 RCT

no

serious

risk of

bias

no serious

inconsistency

no serious

indirectness

very

serious1,2

none 49 51 -

MD 1.3 higher

(4.38 lower to

6.98 higher)

LOW IMPORTANT

1

Few participants (GRADE give suggested recommendation for imprecision : total population size is less than 400 (a threshold rule-of-thumb value; using

the usual I± and I², and an effect size of 0.2 SD, representing a small effect).

2

Only one study, unknown reproducibility

MD: Mean difference; eGFR: estimated glomerular filtration rate

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Table 22d: GRADE profiles for ‘clinical effectiveness’ – activities of daily living

Quality assessment No

of patients Effect

Quality Importance

No

of

studies Design

Risk of

bias Inconsistency Indirectness Imprecision

Other consid-

erations

Activity of

daily living:

exercise

Control

Relative

(95%

CI)

Absolute

Change in max work rate at 3 months (follow-up 3 months; measured with: Watts on reclining ergometer; Better indicated by lower values)

1 RCT

serious

risk of

bias1

no serious

inconsistency

no serious

indirectness2

very

serious3,4

none 37 9 -

MD 3 higher

(7.66 lower to

13.66 higher)

VERY

LOW

IMPORTANT

Change in peak oxygen uptake at 3 months (follow-up 3 months; measured with: VO2

peak ml/min/kg; Better indicated by higher values)

1 RCT

serious

risk of

bias1

no serious

inconsistency

no serious

indirectness2

very

serious3,4

none 37 9 -

MD 1.00 lower

(2.46 lower to

0.46 higher)

VERY

LOW

IMPORTANT

1

Unclear how randomization and allocation was performed.

2

Unclear how well this test represent the patients' ability to manage activity of daily living.

3

Only one study, unknown reproducibility

4

Few participants (GRADE give suggested recommendation for imprecision : total population size is less than 400 (a threshold rule-of-thumb value; using

the usual α and β, and an effect size of 0.2 SD, representing a small effect).

MD: Mean difference; VO2

peak: peak oxygen uptake

Table 22e: GRADE profiles for ‘clinical effectiveness’ - health related quality of life and pa-

tient satisfaction

Quality assessment No

of patients Effect

Quality Importance

No

of

studies Design

Risk of

bias Inconsistency Indirectness Imprecision

Other consider-

ations

Renal denerva-

tion Control

Relative

(95%

CI)

Absolute

Quality of Life: generic (Better indicated by lower values)

No evidence available IMPORTANT

Quality of Life: disease specific (Better indicated by higher values)

No evidence available IMPORTANT

Patient satisfaction (Better indicated by higher values)

No evidence available IMPORTANT

Patient willingness to undergo renal denervation

No evidence available IMPORTANT

Change in need for medication (Better indicated by lower values)

Assessed narratively as No change (Gosain 2013) IMPORTANT

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List of ongoing and planned studies

We performed searches in the WHO ITRP (International Clinical Trials Registry Platform) on

2.10.2013 with the following search combinations: Hypertension (in title) AND Denervation

or catheter ablation (in intervention) which resulted in 65 records for 64 trials and Renal or

kidney (in title) AND Hypertension (condition) AND Denervation or catheter ablation (Inter-

vention) which resulted in 64 records for 63 trials. Out of these, 26 controlled studies were

identified by 1 person and are listed in the table below.

Input from dedicated reviewers identified additionally 4 ongoing trials on renal denervation.

They are added at the end of the table.

Table 23: Ongoing and planned studies

ID Study name

Health condition

(selected inclusion

criteria)

Target sample size

Intervention Control Primary

outcomes

NCT01911078

Renal Sympathetic

Denervation for Treat-

ment of Metabolic

Syndrome Associated

Hypertension (Metabol-

ic Syndrome Study)

Metabolic Syndrome

Uncontrolled Hyperten-

sion

N=60

Device: En-

ligHTN™ Renal

Denervation

System.

Procedure: Renal

Denervation

NR

Study described as:

Allocation: Random-

ised, Endpoint Classi-

fication: Efficacy

Study, Intervention

Model: Parallel As-

signment, Masking:

Open Label, Primary

Purpose: Treatment

Insulin re-

sistance

BP 3 and 12

months

NCT01918111

Effects of ReEnal De-

nervation for Resistant

Hypertension on Exer-

cise Diastolic Function

and Regression of

Atherosclerosis and the

Evaluation of NEW

Methods Predicting A

successfulL Renal

Sympathetic Denerva-

tion (RENEWAL-

EXERCISE, -REGRESS,

and -PREDICT Trial

From RENEWAL RDN

Registry)

Systolic BP>140 mmHg

(>130 mmHg for diabe-

tes) or diastolic

BP>90mmHg (>80

mmHg for diabetes)

despite adequate

administration of ≥3

different classes of

anti-hypertensives

N=52

Procedure: Renal

denervation

Drug: adenosine

infusion treatment

Study described as:

Allocation: Random-

ised, Intervention

Model: Crossover

Assignment, Mask-

ing: Open Label,

Primary Purpose:

Treatment

Change in

coronary

atheroma (24

months)

NCT01903187

Multi-center, Random-

iszed, Single-blind,

Sham Controlled Clini-

cal Investigation of

Renal Denervation for

Uncontrolled Hyperten-

sion

Office Systolic BP = 160

mmHg (office Systolic

BP = 150mmHg for

DM2)

N=590

Device: En-

ligHTN™ Renal

Denervation

Other: Sham

Reduction of

Office Systolic

BP (6 months)

Proportion of

subjects who

experience any

Major Adverse

Event

NCT01897545

Combined Treatment of

Arterial Hypertension

and Atrial Fibrillation

Arterial Hypertension

Atrial Fibrillation

N=60

Procedure: PVI +

renal denervation

Procedure: Circum-

ferential PVI

Freedom of AF

or other atrial

arrhythmias

(1 year)

Systolic BP

lowering

(1year)

NCT01874470

Allegro-HTN

Renal Denervation by

Allegro System in

Patients With Resistant

Hypertension

Resistant hypertension

N=160

Procedure: Renal

denervation

Other: standard

medication

Change in

office-based

systolic BP

(SBP) (6

months)

NCT01865240 Renal Denervation for

Resistant Hypertension

systolic BP =140mmHg

or 130mmHg for pa-

tients with diabetes

Concurrent treatment

with 3 anti-

hypertensive drugs

N=100

Procedure: Renal

Denervation

NR

Study described as:

Allocation: Random-

ised, Endpoint Classi-

fication: Safe-

ty/Efficacy Study,

Intervention Model:

Parallel Assignment,

Masking: Open Label,

BP control (6

months)

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ID Study name

Health condition

(selected inclusion

criteria)

Target sample size

Intervention Control Primary

outcomes

Primary Purpose:

Treatment

NCT01850901

Renal Sympathetic

Denervation as a New

Treatment for Therapy

Resistant Hypertension

Mean day-time SBP =

135 mmHg (ABPM),

while using 3 or more

antihypertensives

N=300

Procedure: Renal

sympathetic

denervation

NR

Study described as:

Allocation: Random-

ised, Endpoint Classi-

fication: Safe-

ty/Efficacy Study,

Intervention Model:

Parallel Assignment,

Masking: Open Label,

Primary Purpose:

Treatment

Change in BP

(measured by

ABPM) (6

months)

NCT01713270

Renal Sympathetic

Denervation in Patients

With Drug-resistant

Hypertension and

Symptomatic Atrial

Fibrillation

N=100

Procedure: Di-

rect-Current

Cardioversion

Procedure: renal

sympathetic

denervation

NR

Study described as:

Allocation: Random-

ised, Endpoint Classi-

fication: Safe-

ty/Efficacy Study,

Intervention Model:

Parallel Assignment,

Masking: Single Blind

(Outcomes Assessor),

Primary Purpose:

Treatment

Change in

atrial fibrilla-

tion burden

(12 months)

NCT01673516

Effect of Renal Sympa-

thetic Denervation on

Resistant Hypertension

and Cardiovascular

Hemodynamic in Com-

parison to Intensive

Medical Therapy Utiliz-

ing Impedance Cardi-

ography

Average SBP

>140mmHg, measured

per guidelines

≥3 antihypertensives

N=60

Device: The

HOTMAN® Sys-

tem

Procedure: The

Symplicity® Renal

Denervation

System

NR

Study described as:

Allocation: Random-

ised, Endpoint Classi-

fication: Safe-

ty/Efficacy Study,

Intervention Model:

Parallel Assignment,

Masking: Open Label,

Primary Purpose:

Treatment

Absolute

change in

office systolic

BP (SBP)

(6 months)

NCT01656096

Renal Sympathetic

Denervation in Mild

Refractory Hyperten-

sion

Refractory hyperten-

sion: 3 or more antihy-

pertensive agents of

different classes

(including a diuretic)

N=70

Device: Renal

sympathetic

denervation

(Symplicity®

ablation catheter,

Medtronic Inc.

Minneapolis,

Minnesota, USA)

Other: Sham proce-

dure

Change in

systolic BP

(ABPM mean

value)

(6 months)

NCT01635998

Adjunctive Renal Sym-

pathetic Denervation to

Modify Hypertension as

Upstream Therapy in

the Treatment of Atrial

Fibrillation

History of AF planned

catheter ablation pro-

cedure

Hypertension (SBP =160

mm Hg and/or DBP

=100 mmHg) and

receiving treatment

with at least one anti-

hypertensive medica-

tion

N=300

Procedure: Renal

sympathetic

denervation

NR

Study described as:

Allocation: Random-

ised, Endpoint Classi-

fication: Safe-

ty/Efficacy Study,

Intervention Model:

Parallel Assignment,

Masking: Double

Blind (Subject, Out-

comes Assessor),

Primary Purpose:

Treatment

Anti-

arrhythmic

drug (AAD)-

free single-

procedure

freedom from

atrial fibrilla-

tion recurrence

(12 months)

NCT01644604

Renal Denervation by

MDT-2211 System in

Patients With Uncon-

trolled Hypertension

≥3 anti-hypertensives

of which one must be a

diuretic

Office systolic BP (SBP)

of = 160 mmHg

N=100

Device: MDT-

2211 Renal

Denervation

System

NR

Study described as:

Allocation: Random-

ised, Endpoint Classi-

fication: Safe-

ty/Efficacy Study,

Intervention Model:

Parallel Assignment,

Masking: Open Label,

Primary Purpose:

Treatment

Change in

Office Systolic

BP (6 months)

NCT01628172

Renal Sympathetic

Denervation for the

Management of Chron-

ic Hypertension

Uncontrolled hyperten-

sion (SBP = 140 mmHg

during 24H ABPM)

>= 3 anti-hypertensive

drugs (including at

least one diuretic)

N=100

Device: Biosense

Webster Celcius

Thermacool®

catheter

NR

Study described as:

Allocation: Random-

ised, Endpoint Classi-

fication: Safe-

ty/Efficacy Study,

Intervention Model:

Parallel Assignment,

Change in 24h

ABPM (6

months)

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ID Study name

Health condition

(selected inclusion

criteria)

Target sample size

Intervention Control Primary

outcomes

Masking: Single Blind

(Subject), Primary

Purpose: Treatment

NTR3444

Comparison of renal

sympathetic denerva-

tion with spironolac-

tone in patients with

still a high BP despite

the use of 3 different

antihypertensive

agents.

Hypertension, Renal

sympathetic denerva-

tion, Spironolactone

N=120

The intervention

consists of

endovascular

renal sympathet-

ic denervation

Addition of spirono-

lactone to existing

antihypertensive

treatment.

Difference in

24h ABPM -

between spiro-

nolactone and

renal denerva-

tion (6

months)

NCT01570777 Renal Denervation in

Hypertension

Office BP =140 and/or

90 mmHg

≥ 3 anti-hypertensives

including a diuretic

N=120

Procedure: renal

denervation and

optimised medi-

cation regimen

Procedure: optimised

medication regimen

Cost-

effectiveness

evaluation (1

year)

Mean diurnal

systolic BP

assessed by

ABPM (6

months)

NCT01522430

Study of Catheter Based

Renal Denervation

Therapy in Hyperten-

sion

> 3 antihypertensives

including a thiazide

or a loop diuretic and

at least one attempt to

treat with spironolac-

tone

Daytime ABPM 135

mmHg and/or 85

mmHg, respectively, is

acceptable for inclusion

in

the study if the patient

takes four or more

antihypertensive medi-

cations

N=120

Procedure: Renal

angiography

followed by renal

sympathetic

denervation

Procedure: Renal

angiography alone

Ambulatory

systolic and

diastolic BP (6

months)

Glomerular

filtration rate

(6 months)

NCT01505010

Renal Denervation for

Management of Drug-

Resistant Hypertension

Under maximal thera-

py, the 24-h ambulato-

ry BP should be 130

mm Hg

systolic or 80 mm Hg

diastolic or higher.

N=84

Procedure: Renal

denervation

NR

Study described as:

Allocation: Random-

ised, Endpoint Classi-

fication: Safe-

ty/Efficacy Study,

Intervention Model:

Parallel Assignment,

Masking: Single Blind

(Outcomes Assessor),

Primary Purpose:

Treatment

Decrease in

systolic BP on

daytime ambu-

latory meas-

urement (36

months)

NCT01418261

Renal Denervation in

Patients With Uncon-

trolled Hypertension

(SYMPLICITY HTN-3)

≥3 anti-hypertensives

one must be a diuretic

Office systolic BP (SBP)

of 160 mmHg

N=530

Device: Renal

denervation

(Symplicity®

Catheter System)

NR

Study described as:

Allocation: Random-

ised, Endpoint Classi-

fication: Safe-

ty/Efficacy Study,

Intervention Model:

Parallel Assignment,

Masking: Single Blind

(Subject), Primary

Purpose: Treatment

Change in

Office Systolic

BP (6 months)

Incidence of

Major Adverse

Events through

1 month post-

randomisation

(Renal artery

stenosis

measured at 6

months)

NCT01390831

Renal Denervation in

Patients With Uncon-

trolled Hypertension in

Chinese

Systolic BP of 160

mmHg or more and/or

a diastolic BP of

90 mmHg or more

Receiving and adhering

to at least ≥ 3 appro-

priate antihyperten-

sives

N=100

Device: THER-

MOCOOL® Cathe-

ter

NR

Study described as:

Allocation: Non-

Randomised, End-

point Classification:

Safety/Efficacy Study,

Intervention Model:

Parallel Assignment,

Masking: Single Blind

(Outcomes Assessor),

Primary Purpose:

Treatment

BP Reduction

(1year)

NCT01366625

Renal Denervation in

Patients With Resistant

Hypertension and

Obstructive Sleep

Systolic BP ≥140 mmHg

(office);

≥3 antihypertensives

(including diuretic)

Device: Renal

denervation with

a catheter-based

procedure (Sym-

NR

Study described as:

Allocation: Random-

ised, Endpoint Classi-

BP Reduction

(3 months)

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ID Study name

Health condition

(selected inclusion

criteria)

Target sample size

Intervention Control Primary

outcomes

Apnea

N=100

plicity® Catheter

System)

fication: Efficacy

Study, Intervention

Model: Parallel As-

signment, Masking:

Open Label, Primary

Purpose: Treatment

NCT01117025

Combined Treatment of

Resistant Hypertension

and Atrial Fibrillation

N=26

Procedure: Cir-

cumferential PV

isolation

Procedure: Cir-

cumferential

PVI+renal dener-

vation

Allocation: Random-

ized, Endpoint Classi-

fication: Safe-

ty/Efficacy Study,

Intervention Model:

Parallel Assignment,

Masking: Double

Blind (Subject, Out-

comes Assessor),

Primary Purpose:

Treatment

Pokushalov,

INCLUDED

NCT00888433

Renal Denervation in

Patients With Uncon-

trolled Hypertension

(Symplicity HTN-2)

N=106

Device: Renal

Denervation

(Symplicity®

Catheter System)

Allocation: Random-

ised, Endpoint Classi-

fication: Safe-

ty/Efficacy Study,

Intervention Model:

Parallel Assignment,

Masking: Open Label,

Primary Purpose:

Treatment

Published HTN-

2

INCLUDED

NTR4109 Ablation of Sympathetic

Atrial Fibrillation

Atrial Fibrillation, High

BP

N=243

Recruitment pending

Procedure: Renal

artery denerva-

tion

Renal artery

denervation and

pulmonary vein

isolation

Pulmonary vein

isolation

Time to first

detection of

atrial fibrilla-

tion >30

seconds, with

the monitoring

period starting

3 months after

the interven-

tion

NCT01785732

Renal Sympathetic

Denervation and Insulin

Sensitivity (RENSYMPIS

Study)

Resistant Hypertension

(systolic BP >160mmHg

and 3 or more

antihypertensive agents

in use

N=60

Procedure: Renal

Denervation

NR

Study described as:

Allocation: Random-

ised, Endpoint Classi-

fication: Safe-

ty/Efficacy Study,

Intervention Model:

Parallel Assignment,

Masking: Open Label,

Primary Purpose:

Treatment

Office BP

(2 years)

NCT01848275

Full Length Versus

Proximal Renal Arteries

Ablation

Office systolic BP of

160 mm Hg or more,

≥3 antihypertensives

N=40

Device: Thermo-

cool® catheter

NR

Study described as:

Allocation: Random-

ised, Endpoint Classi-

fication: Safe-

ty/Efficacy Study,

Intervention Model:

Parallel Assignment,

Masking: Open Label,

Primary Purpose:

Treatment

BP (1 year)

NCT01888315

Influence of Catheter-

based Renal Denerva-

tion in Diseases With

Increased Sympathetic

Activity

Patient scheduled for

renal sympathetic

denervation using

market-released device.

N=1000

Renal denerva-

tion with En-

ligHTNTM

St. Jude

Medical

Renal denerva-

tion with Paradi-

seTM

ReCor Medi-

cal

Renal denerva-

tion with Sym-

plicity® Flex

Medtronic/Ardian

Renal denerva-

tion with Vessix

V2TM

Boston

Scientific

Described as non-

randomised

Safety and

efficacy of

renal denerva-

tion (6

months)

NCT01560312

Renal Denervation in

Refractory Hyperten-

sion PRAGUE-15

Hypertension, Resistant

to Conventional Thera-

py

Device: Renal

denervation

(Symplicity®

Study described as:

Allocation: Random-

ised, Endpoint Classi-

BP difference

(6 months, 5

years)

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ID Study name

Health condition

(selected inclusion

criteria)

Target sample size

Intervention Control Primary

outcomes

N=150

Catheter Sys-

tem™)

fication: Efficacy

Study, Intervention

Model: Single Group

Assignment, Mask-

ing: Open Label,

Primary Purpose:

Treatment

NCT01459900

Renal Sympathectomy

in Treatment-resistant

Essential Hypertension,

a Sham Controlled

Randomized Tri-

al ReSET

Hypertension (Systolic

daytime ambulatory BP

at least 145 mmHg and

compliance to a mini-

mum of 3

antihypertensive drugs,

including a diuretic, or

in case of diuretic

intolerance at

least 3 nondiuretic

antihypertensive

drugs.)

N=70

Procedure: Renal

angiography

Procedure: Renal

artery ablation

Study described as:

Allocation: Random-

ised, Endpoint Classi-

fication: Efficacy

Study, Intervention

Model: Parallel As-

signment, Masking:

Double Blind (Sub-

ject, Caregiver),

Primary Purpose:

Treatment

Daytime systol-

ic BP assessed

by 24 hours

ambulatory BP

measurement

(3 months)

EudraCT 2012-

001066-14

Sympathetic renal

denervation versus

increment of pharma-

cological treatment in

resistant arterial hyper-

tension

DENERVHTA

Subjects with diag-

nosed resistant arterial

hypertension (office BP

≥ 140 and/or 90 mmHg

despite ≥3 antihyper-

tensive drugs given at

the maximum tolerated

therapeutic dosage,

one diuretic), for at

least the last 3 months.

N=50

Percutaneous

catheter-based

renal sympathet-

ic denervation

Addition of spirono-

lactone to the base-

line pharmacological

treatment

Change in

ambulatory

24h-systolic BP

(SBP) from

baseline (Visit

0) to Final

Examination (6

months).

EudraCt 2011-

004995-13

Endovascular renal

sympathetic denerva-

tion versus spironolac-

tone for treatment-

resistant hypertension:

a randomized, multi-

centric study

Treatment-resistant

hypertension

N=130

Endovascular

renal sympathet-

ic denervation

Spironolactone (up to

50 mg)

Difference in

24-hour ambu-

latory BP

decrease

between the

RFSD and

spironolactone

group (6

months)

ABPM-ambulatory blood pressure monitoring; BP: blood pressure; mmHg: millimetre mercury; DM: diabetes mellitus;

PVI: pulmonary vein isolation; AF: atrial fibrillation; SBP: systolic blood pressure; NR: not reported; ABPM: ambulato-

ry blood pressure monitoring; DBP: diastolic blood pressure; AAD: anti-arrythmic drug

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Applicability table

Table 24: Summary table characterising the applicability of the body of evidence

Domain Description of applicability of evidence

Population

The major studies included patients older than 18 years, with office based SBP of

≥160 mm Hg despite use of at least 3 antihypertensive drugs at adequate dose (in-

cluding one diuretic). They excluded patients with secondary causes of hypertension,

type 1 diabetes, renovascular abnormalities, reduced kidney function (eGFR <45

ml/min/1.73 m2

by modification of diet in renal disease criteria).

These criteria seem to be in accordance with the intended patient population of

treatment-resistant hypertensions. The need for normal renal nerve anatomy/access

is necessary based on how the procedure is performed.

Intervention

Renal denervation was performed in addition to continuation of full pharmaceutical

treatment.

The procedure requires delivery of radiofrequency along the renal arteries to result

in denervation. There is no immediate way to determine if the ablation has been

successful. Currently the Symplicity® catheter has been used in most of the con-

trolled studies, but other catheters are currently being explored. There may or may

not be differences in efficacy and safety depending on the catheter used and mode

of ablation.

The surgeon’s technical expertise could influence the risk for local side effects. If

being introduced as a new treatment method in European hospitals, the procedure

will (as all new interventions) be accompanied by a learning curve.

Comparators

The comparator in the controlled studies was either no intervention or sham treat-

ment. Both intervention and control group continued with standard pharmacological

treatment. As the inclusion criteria was treatment-resistant hypertension despite at

least 3 different drugs, one could argue that addition of further classes of antihyper-

tensive drugs, change in dosing or other interventions might have been a valid alter-

native. However, Gosain and colleagues reported that the average number of antihy-

pertensive medications was 5 in most studies so it may be difficult to find a suitable

pharmacological comparator (Gosain 2013).

Outcomes

Short-term outcomes and surrogate outcomes have been used in the studies while

important clinical endpoints (overall mortality, cardiovascular mortality and major

events like stroke, myocardial infarction and heart failure) have not been analysed.

Neither have the studies focused on how this intervention may affect outcomes such

as patient satisfaction, quality of life and activities of daily living. The full clinical

benefit is therefore unknown.

Setting

Participants in the studies were recruited from secondary or tertiary care in Europe,

Australia and USA. This probably reflects the setting in which this intervention may

typically be used.

Study duration was 3 to 12 months in the controlled trials. However, some exten-

sions or uncontrolled trials used other durations. As hypertension usually requires

continued follow-up over an extensive time-frame this is also relevant for renal de-

nervations to be able to detect changes over time.

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APPENDIX 2: RESULT CARDS

Health Problem and Current Use of the Technology

A0001: For which indication or for what purposes is renal denervation used, and are

there any contra-indications?

Methods

See general description of methods (Appendix 1)

Source of information:

Basic search

Domain search

Other: additional search for guidelines in pubmed, searching reference lists

Critical appraisal criteria not applicable

Method of synthesis: narrative

Result

An expert consensus document with the contribution from 11 European countries published

in 2013 from the European Society of Cardiology on catheter-based renal denervation forms

the basis for the following criteria that patients should comply with before renal denervation

is considered (Mahfoud 2013a):

Office-based systolic BP ≥ 160 mm Hg (≥150 mm Hg diabetes type 2) despite use of ≥3

antihypertensive drugs in adequate dosage and combination (incl. diuretic)

Treatment resistance to lifestyle modification

Exclusion of secondary hypertension

Exclusion of pseudo-resistance using ambulatory BP monitoring (average BP >130 mm Hg

or mean daytime BP >135 mm Hg)

Preserved renal function (glomerular filtration rate ≥45 ml/min/1.73 m2

)

Eligible renal arteries: no polar or accessory arteries, no renal artery stenosis, no prior

revascularization

A position paper from the European Society of Hypertension published in 2012 (Schmieder

2012) describe criteria which are generally in accordance with the above. Patients are eligible

if they have:

“…(severe) treatment-resistant hypertension defined by office SBP at least 160 systolic

(>150 mm Hg in type 2 diabetes) despite treatment with at least three antihypertensive

drugs of different types in adequate doses, including one diuretic, which is equivalent to

stage 2 or 3 hypertension”.

Pseudoresistance have to be excluded

Non-adherence to drug therapy must be refuted

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“Persisting high office BP in spite of drug treatment should be confirmed with home and

most importantly with 24-h ambulatory BP monitoring, since up to one-third of treat-

ment-‘resistant’ hypertensive patients have normal BP outside the office (false resistant

hypertension due to persisting white-coat effect during treatment)”

Identification of contributing lifestyle factors must be made along with screening for

secondary causes of hypertension in order to attempt to control BP by removal.

The following contraindications are described in the above papers:

Previous renal artery intervention (balloon angioplasty or stenting)

Evidence of renal artery atherosclerosis (defined as a renal artery stenosis > 50 %)

Presence of multiple main renal arteries in either kidneys or main renal arteries of < 4

mm in diameter or <20 mm in length

Patients should be in stable clinical conditions (RDN is not an emergency treatment), thus

ruling out patients with recent myocardial infarction, unstable angina pectoris, or a cere-

brovascular accident within the past 3–6 months.

Discussion

-

References

Mahfoud F. Expert consensus document from the European Society of Cardiology on cathe-

ter-based renal denervation. Eur Heart J. 2013a;34(28):2149-57.

Schmieder RE, Redon J, Grassi G, Kjeldsen SE, Mancia G, Narkiewicz K et al. ESH Position Pa-

per: Renal denervation – an interventional therapy of resistant hypertension. J Hypertens.

2012;30(5):837-41.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

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A0002: What is the precise definition of treatment-resistant arterial hypertension and

which diagnosis is given according to ICD-10?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic search

Domain search

Other: additional search for guidelines and searching WHO in relation to ICD-10, and

PubMed.

Critical appraisal criteria not applicable

Method of synthesis: narrative

Result

Guidelines from the ESH and the ESC (Mancia 2013) present the following definitions and

classification of office BP levels (mm Hg)*:

Classification of office BP levels (mm Hg)

Category Systolic Diastolic

Optimal <120 and <80

Normal 120 – 129 and/or 80 – 84

High normal 130 – 139 and/or 85 – 89

Grade 1 hypertension 140 - 159 and/or 90 – 99

Grade 1 hypertension 160 – 179 and/or 100 – 109

Grade 1 hypertension >180 and/or >110

Isolated systolic hypertension >140 and <90

* The blood pressure (BP) category is defined by the highest level of BP, whether systolic or diastolic. Isolated systol-

ic hypertension should be graded 1, 2, or 3 according to systolic BP values in the ranges indicated.

The condition resistant hypertension appears when appropriate treatment including lifestyle

measures and three antihypertensive drugs (one of them being a diuretic) fails to lower Sys-

tolic BP and Diastolic BP values to 140 and 90 mm Hg respectively. All drug agents should be

prescribed at optimal dose amounts (Calhoun 2008).

There is no designation for ‘‘resistant hypertension’’ in the ICD-10 despite the increasing

recognition of resistant hypertension as a major clinical entity (Giles, 2012). Resistant hyper-

tension has been designated as 997.91 in the ICD-9 codes. Giles et al. notes the unfortunate

development in the fact that resistant hypertension no longer can be classified as it should

be in relation to its complexity. Giles continues by recommending that resistant hyperten-

sion must be dealt with by adding complexity of illness codes. For now “resistant hyperten-

sion” can be classified in the category “I99: Other and unspecified disorders of circulatory

system” using the ICD-10 Version: 2010 (WHO 2010).

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Discussion

-

References

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD. Resistant hypertension: diag-

nosis, evaluation, and treatment: a scientific statement from the American Heart Association

Professional Education Committee of the Council for High Blood Pressure Research. Circula-

tion. 2008;117(25):e510-26.

Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M. 2013 ESH/ESC guidelines

for the management of arterial hypertension: the Task Force for the Management of Arterial

Hypertension of the European Society of Hypertension (ESH) and of the European Society of

Cardiology (ESC). Eur Heart J. 2013;34(28):2159-219.

Giles TD, Sander GE. The new International Classification of Diseases (ICD-10): the hyperten-

sion community needs a greater input. J Clin Hypertens (Greenwich). 2012;14(1):1-2.

WHO: International Statistical Classification of Diseases and Related Health Problems 10th

Revision (ICD-10) Version for 2010. Available at:

http://apps.who.int/classifications/icd10/browse/2010/en#/I99

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

A0003: What are the known risk factors for treatment-resistant arterial hypertension?

Methods

See general description of methods (Appendix 1)

Other, please specify:

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Source of information:

Basic search

Domain search

Other: additional search for guidelines

Critical appraisal criteria not applicable

Method of synthesis: narrative

Result

Resistant hypertension can be real or only apparent. Apparent or pseudo-resistant hyperten-

sion is e.g. caused by non-adherence to medicine. The ESH and the ESC have divided risk

factors for real or true resistant hypertension into five categories (Mancia 2013):

Lifestyle factors: obesity or large weight gains, excessive alcohol consumption, high so-

dium intake

Chronic intake of vasopressor or sodium-retaining substances

Obstructive sleep apnoea

Undetected secondary forms of hypertension

Advanced and irreversible organ damage, particularly when it involves renal function or

leads to a marked increase in arteriolar wall–lumen ratio or reduction of large artery dis-

tensibility.

The American Heart Association (AHA) identifies older age and obesity as the strongest risk

factors for resistant hypertension (Calhoun 2008). Comparing a group of >75 year old pa-

tients to <60 old patients revealed significantly more patients in the older age group not

having their BP controlled after treatment. Using diastolic BP as reference patients being

obese didn’t experience treatment success as often as non-obese patients. AHA has tabulat-

ed the following characteristics associated with resistant hypertension:

Older age

High baseline BP

Obesity

Excessive dietary salt ingestion

Chronic kidney disease

Diabetes

Left ventricular hypertrophy

Black race

Female sex

Residence in South Eastern United States

Discussion

-

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References

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD. Resistant hypertension: diag-

nosis, evaluation, and treatment: a scientific statement from the American Heart Association

Professional Education Committee of the Council for High Blood Pressure Research. Circula-

tion. 2008;117(25):e510-26.

Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M. 2013 ESH/ESC guidelines

for the management of arterial hypertension: the Task Force for the Management of Arterial

Hypertension of the European Society of Hypertension (ESH) and of the European Society of

Cardiology (ESC). Eur Heart J. 2013;34(28):2159-219.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

A0004: What is the natural course of treatment-resistant arterial hypertension?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic search

Domain search

Other: additional search for guidelines

Critical appraisal criteria not applicable

Method of synthesis: narrative

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Result

The natural course for particularly resistant hypertension has been inadequately appraised.

Hypertension will if untreated increase the risk of e.g. cardiovascular disease, stroke and

renal failure. The risk increases with higher BP, duration of hypertension and other risk fac-

tors. The natural course or prognosis is probably impaired as the patient typically has en-

dured a longlasting and poorly controlled hypertension.

The patients frequently have to face associated cardiovascular risk factors such as diabetes,

obstructive sleep apnea and left ventricular hypertrophy (Calhoun 2013).

Discussion

-

References

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD. Resistant hypertension: diag-

nosis, evaluation, and treatment: a scientific statement from the American Heart Association

Professional Education Committee of the Council for High Blood Pressure Research. Circula-

tion. 2008;117(25):e510-26.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

A0005: What is the burden of treatment-resistant arterial hypertension for the patient?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

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Basic search

Domain search

Other: additional search for guidelines

Critical appraisal criteria not applicable

Method of synthesis: narrative

Result

Hypertension itself usually is not noticed by the patient (Calhoun 2008) and the patient nor-

mally present with no symptoms. Some patients might experience fatigue or headache. Oth-

ers might experience nosebleed. The higher the BP is the higher the likelihood that the pa-

tient exhibit symptoms of hypertension. Result cart A0001 – “For which indication or for what

purposes is renal denervation used” describes criteria for considering renal denervation. Re-

sult card A0004: “What is the natural course of treatment-resistant arterial hypertension?”

describe some of the possible long term consequences for the patient when the condition

cannot be treated.

Discussion

-

References

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD. Resistant hypertension: diag-

nosis, evaluation, and treatment: a scientific statement from the American Heart Association

Professional Education Committee of the Council for High Blood Pressure Research. Circula-

tion. 2008;117(25):e510-26.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

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A0006: What is the burden of treatment-resistant arterial hypertension for society in

terms of prevalence, incidence and costs?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic search

Domain search

Other: additional search for guidelines and in pubmed

Critical appraisal criteria not applicable

Method of synthesis: narrative

Result

Overall the exact prevalence of resistant hypertension is unknown (Calhoun, 2008), but it is

assumed to be a commen clinical condition. In an older and more obese population the

prevalence is expected to increase (Jentzer 2013). Jentzer et al. reports in an American popu-

lation that approximately 5-10 % of patients with inadequately-controlled Hypertension have

resistant Hypertension, defined as BP above goal despite use of ≥3 antihypertensive drugs in

adequate dosage and combination (incl. diuretic) (Jentzer 2013). The ESH and the ESC report

that depending on the population examined and the level of medical screening, the preva-

lence of resistant hypertension has been reported to range from 5–30 % of the overall hyper-

tensive population, but probably less than 10 % (Mancia 2013). The prevalence of hyperten-

sion (all cases) is estimated to be approximately 30–45 % of the general population. The

prevalence increases with older age. One should be aware about differences in BP across

countries (Mancia 2013). The Regional HTA Centre in Vastra Gotaland, Sweden reports that

the prevalence of resistant hypertension may be 2 – 6 % in an adult general population based

on literature and figures of prevalence (Andersson 2013).

No literature has been found on the specific costs of resistant hypertension.

Discussion

Above data/ statistics are subject to uncertainty and should only cautiously be used in fur-

ther analysis.

References

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD. Resistant hypertension: diag-

nosis, evaluation, and treatment: a scientific statement from the American Heart Association

Professional Education Committee of the Council for High Blood Pressure Research. Circula-

tion. 2008;117(25):e510-26.

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EUnetHTA JA2 Renal denervation systems or treatment-resistant hypertension WP5B

Dec2013 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 95

Jentzer J, Batal O, Rao S, Rahman A. Resistant Hypertension: A Comprehensive Overview. J

Hypertens 2013, 2:1

Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M. 2013 ESH/ESC guidelines

for the management of arterial hypertension: the Task Force for the Management of Arterial

Hypertension of the European Society of Hypertension (ESH) and of the European Society of

Cardiology (ESC). Eur Heart J. 2013;34(28):2159-219.

Andersson B, Herlitz H, Manhem K, Zachrisson K, VöLz S, Daxberg EL, et al. Renal sympathet-

ic denervation in patients with therapy resistant hypertension.: The Regional Health Technol-

ogy Assessment Centre (HTA-centrum), Region Vastra Gotaland; 2013.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

A0007: What is the target population in this assessment?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic search

Domain search

Other: additional search for guidelines

Critical appraisal criteria not applicable

Method of synthesis: narrative

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Dec2013 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 96

Result

As refered in result card A0001regarding which indication or for what purposes renal de-

nervation is used the target population is patients suffering from resistant hypertension, a

condition which links to sympathetic nervous system overactivity involving the kidneys

(Schmieder 2012). Patients found eligible for the intervention can be treated with catheter-

based renal denervation. The goal of the treatment is prevention of hypertensive end-organ

damage and reduction of cardiovascular morbidity and mortality (Mahfoud 2011a)

The European Society of Hypertension (ESH) and the European Society of Cardiology (ESC)

emphasise the importance of investigating/ try to understand what makes renal denervation

effective or ineffective (patient characteristics or failure to achieve renal sympathectomy)

(Mancia 2013).

Discussion

-

References

Schmieder RE, Redon J, Grassi G, Kjeldsen SE, Mancia G, Narkiewicz K et al. ESH Position Pa-

per: Renal denervation – an interventional therapy of resistant hypertension. J Hypertens.

2012;30(5):837-41.

Mahfoud F, Himmel F, Ukena C, Schunkert H, Böhm M, Weil J. Treatment strategies for re-

sistant arterial hypertension. Dtsch Arztebl Int. 2011a;108(43):725-31.

Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M. 2013 ESH/ESC guidelines

for the management of arterial hypertension: the Task Force for the Management of Arterial

Hypertension of the European Society of Hypertension (ESH) and of the European Society of

Cardiology (ESC). Eur Heart J. 2013;34(28):2159-219.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

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Dec2013 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 97

A0011: What is the expected annual utilization of renal denervation?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic search

Domain search

Other: additional search for guidelines, PubMed and Google searches

Critical appraisal criteria not applicable

Method of synthesis: narrative

Result

Two factors make it quite difficult to come up with a reasonable estimate on the expected

annual utilization of the procedure: 1) the uncertain figures of prevalence and 2) the poten-

tial number of candidates based on indications/contraindications for the surgical procedure.

As indicated earlier in result card A0006 the figures of resistant hypertension in a general

adult population is uncertain, so is the number of candidates extracted from the “resistant

hypertension” group as surgical candidates based on the criteria described in result card

A0001. Figures indicate potentially many candidates for renal denervation. More research,

experience and time will add data to the expected annual utilization of renal denervation.

Discussion

-

References

-

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

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EUnetHTA JA2 Renal denervation systems or treatment-resistant hypertension WP5B

Dec2013 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 98

Completely

Partly

Not

A0020: What is the marketing authorisation status of renal denervation systems?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information: see ‘Description and technical characteristics of technology’ (B0003).

Basic search

Domain search

Other:

Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

Questions regarding marketing authorisation status of renal denervation systems will be

answered in the next section ‘Description and technical characteristics of technology’

(B0003).

Discussion

-

References

-

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

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Dec2013 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 99

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

A0021: What is the reimbursement status of renal denervation systems?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information: see ‘Description and technical characteristics of technology’ (B0003)

Basic search

Domain search

Other: Google search for each specific RDN system

Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

Questions regarding reimbursement status of renal denervation systems are answered in the

next section ‘Description and technical characteristics of technology’ (B0003).

Discussion

-

References

-

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

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Dec2013 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 100

Completely

Partly

Not

A0024: How is treatment-resistant arterial hypertension currently diagnosed according

to published guidelines and in practice?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic search

Domain search

Other: additional search for guidelines and PubMed searches

Critical appraisal criteria not applicable

Method of synthesis: narrative

Result

The American Heart Association appropriately points out that: “The evaluation of patients

with resistant hypertension should be directed toward confirming true treatment resistance;

identification of causes contributing to treatment resistance, including secondary causes of

hypertension; and documentation of target-organ damage.” (Galhoun 2008).

Further, AHA emphasised that most cases of resistant hypertension doesn’t origen in solitary

factors/ causes but is multifactorial in etiology caused by variably factors such as obesity,

excessive dietary sodium intake, obstructive sleep apnea, and chronic kidney disease being

particularly common factors (Calhoun 2008; Mahfoud 2013a).

The diagnostic strategy to identify resistant hypertension requires detailed information on

the patient’s history, a careful and detailed physical examination, laboratory tests (to reveal

associated risk factors – organ damage, alterations of glucose metabolism, renal dysfunc-

tion) (Mancia 2013). Additionally any secondary causes of hypertension should be identified:

e.g. primary aldosteronism and renal artery stenoses of an atherosclerotic nature.

Discussion

-

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EUnetHTA JA2 Renal denervation systems or treatment-resistant hypertension WP5B

Dec2013 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 101

References

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD. Resistant hypertension: diag-

nosis, evaluation, and treatment: a scientific statement from the American Heart Association

Professional Education Committee of the Council for High Blood Pressure Research. Circula-

tion. 2008 Jun 24;117(25):e510-26.

Mahfoud F. Expert consensus document from the European Society of Cardiology on cathe-

ter-based renal denervation. Eur Heart J. 2013a;34(28):2149-57.

Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M. 2013 ESH/ESC guidelines

for the management of arterial hypertension: the Task Force for the Management of Arterial

Hypertension of the European Society of Hypertension (ESH) and of the European Society of

Cardiology (ESC). Eur Heart J. 2013;34(28):2159-219.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

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Dec2013 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 102

Description and Technical Characteristics of Technology

B0001: What is renal denervation and what are the treatment alternatives?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

Domain search

Other: additional search in Google

Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

Most of the renal nerve ablation systems or renal denervation system use use low-level radio

frequency energy to modulate the output of nerves that lie within the renal artery wall and

lead into and out of the kidneys," in order to reduce blood flow and thereby reducing

hypertension by de-activating hyperactive nerves, and without affecting other abdominal,

pelvic, or lower extremity nerves (CADTH 2013). There are however also systems that use

ultrasound for ablation.

The mechanism by which renal sympathetic denervation improves management of BP is

complex and involves the following factors (Wojakowski 2012):

Decreasing efferent sympathetic signaling to kidneys

Reducing norepinephrine spillover

Natriuresis

Increasing renal blood flow

Lowering plasma rennin activity

Decreasing renal afferent signalling and central sympathetic activation

The system’s energy, either through radiofrequency or ultrasound, increases the local

temperature in the limited area of the vascular wall, and leads to ablation of afferent and

efferent sympathetic nerves (Wojakowski 2012).

Currently there are a number of renal denervation (RDN) systems using different treatment

strategies available (Table DTC1):

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DTC1. Different systems for RDN, their manufacturer and regulatory stage

Device Manufacturer CE-marked FDA review

Radiofrequency

Symplicity® Medtronic Y 2014 or 15

MarinR® Medtronic N N

EnligHTN™ St. Jude Medical Y N

Vessix V2™ Boston Scientific Y N

OneShot™ Covidien Y N

Iberis™ Terumo Y N

ThermoCool® Biosense Webster N N

Ultrasound

PARADISE™ ReCor Medical Y N

Y=Yes, N=No

Most of these systems use radiofrequency energy to target renal sympathetic nerves except

for the ultrasound-based Recor’s Paradise system (Mahfoud 2013).

The catheter is introduced through the femoral artery and threaded up, under fluoroscopic

control, into the renal artely lumen. Once in place, a series of 4 to 6 radio frequency treat-

ments are applied within each renal artery to ablate the sympathetic nerves coursing along

the outside of the artery (CADTH 2013). The procedure takes about 40-60 minutes (Mahfoud

2013a). The technology behind delivery of radiofrequency ablation is however evolving with

the introduction of devices that improve time efficiency (Mahfeld 2012).

Ultrasound is being investigated as an alternative to radiofrequency energy to provide more

targeted nerve ablation without the need for direct vessel contact. Currently, only the

PARADISE device of these ultrasound devices is CE-marked. In development for RDN is non-

invasive ultrasound. . A transducer positioned outside the body delivers targeted ultrasound

energy that ‘surrounds’ the artery and treats the nerves located in the vicinity of the vessel.

The idea behind creating a focused energy field around the outside of the artery, is that it

might result in a more complete and effective ablation that does not impact the walls of the

artery (KONA Medical 2013).

Catheters designed to inject therapeutic agents directly and non-systemically through the

renal artery wall, such as the Cricket and Bullfrog Micro-Infusion Catheters (Mercator

MedSystems) are also in development for RDN. The Mercator micro-infusion catheters are CE-

marked in Europe and approved by the FDA.

Current practice and other developments for treatment of resistant hypertension

The Task Force for the management of arterial hypertension of the ESH and the ESC (Mancia

2013) describe in their guideline that most patients with resistant hypertension require the

administration of more than three drugs. In current practice this combination of drugs exist

of a thiazide diuretic, a long-acting calcium channel blocker, an angiotensin-converting

enzyme inhibitor or an angiotensin receptor blocker, and a beta-blocker in patients younger

than 60 years of age (CADTH 2013).

Another alternative to drug treatment is carotid baroreceptor stimulation, which includes

chronic field electrical stimulation of carotid sinus nerves via implanted devices. However,

both renal denervation and carotid baroreceptor stimulation are recommended to be

restricted to resistant hypertensive patients at particularly high risk, after fully documenting

the inefficacy of additional antihypertensive drugs to achieve BP control (Mancia 2013).

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Discussion

-

References

CADTH. Catheter-based renal denervation fortreatment-resistant hypertension. Issues in

emerging Health Technologies CADTH issue 121, March 2013.

KONA medical. Announces initiation of WAVE I study. http://konamedical.com/renal-

denervation-therapy, visited 29.09.13

Mafeld S, Vasdev N, Haslam P. Renal Denervation for Treatment-Resistant HypertensionTher

Adv Cardiovasc Dis. 2012;6(6):245-258. http://www.medscape.com/viewarticle/775538

(Visited 26.11.2013)

Mahfoud F. Expert consensus document from the European Society of Cardiology on

catheter-based renal denervation. Eur Heart J. 2013a;34(28):2149-57.

Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M. 2013 ESH/ESC guidelines

for the management of arterial hypertension: the Task Force for the Management of Arterial

Hypertension of the European Society of Hypertension (ESH) and of the European Society of

Cardiology (ESC). Eur Heart J. 2013;34(28):2159-219.

Wojakowski W, Tendera M, Jadczyk T, Januszewicz A, Witkowski A. Catheter-based renal

denervation. E-journal of the ESC Council for Cardiology Practice. 2012; 10 (22).

http://www.escardio.org/communities/councils/ccp/e-journal/volume10/Pages/catheter-

based-renal-denervation-tendera-m-wojakowksy-w.aspx#.Up2lJ9IyLDs (Visited 26.11.13)

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

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Dec2013 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 105

B0002: What is the approved indication and claimed benefit of renal denervation and the

treatment alternatives?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

Domain search

Other: additional Google search

Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

The European Society of Cardiology’s consensus document states that according to the

available evidence, patients are eligible for renal denervation if they have (severe) treatment-

resistant hypertension defined by office SBP ≥160 mm Hg (≥150 mmHg in type 2 diabetes)

despite treatment with at least three antihypertensive drugs of different types in adequate

doses, including one diuretic (Mahfoud 2013a). In certain centres, uncontrolled BP values

140/90 mm Hg are taken as reference (Mahfoud 2013a). Box DTC1 below describes in more

detail which criteria patients should comply with before renal denervation is considered.

Box DTC1 Criteria patients should comply with before renal denervation is considered

Office-based systolic BP ≥ 160 mmHg (≥150 mm Hg diabetes type 2)

≥3 antihypertensive drugs in adequate dosage and combination (incl. diuretic)

Lifestyle modification

Exclusion of secondary hypertension

Exclusion of pseudo-resistance using ABPM (average BP 130 mm Hg or mean day-

time BP 135 mm Hg)

Preserved renal function (GFR ≥45 ml/min/1.73m2)

Eligible renal arteries: no polar or accessory arteries, no renal artery stenosis, no

prior revascularization

The claimed benefit is that renal denervation results in systolic and diastolic BP reductions.

The risk of cardiovascular death is cut in half with every 20 mm Hg decrease in systolic BP.

RDN trials to date have shown an average reduction of about 25 mm Hg (Fornell 2013).

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Discussion

Mahfoud et al. point out that BP rarely changes immediately after the procedure. It often

takes several weeks to months before a notable BP reduction occurs, suggesting that a slowly

progressive resetting of sympathetic neural regulation occurs (Mahfoud 2013a). Furthermore,

it is stated that renal denervation as currently deployed is designed to improve BP control in

patients whose BP is resistant to control with conventional drug therapy. In this regard, renal

denervation is unlikely to significantly reduce pill burden in most patients and is not a cure

for hypertension. It is an add-on therapy, thus leading to additional health care resources in

terms of the cost of the system, the training of specialist staff, and the use of hospital

radiology services during the procedure (CADTH 2013).

References

CADTH. Catheter-based renal denervation fortreatment-resistant hypertension. Issues in

emerging Health Technologies CADTH issue 121, March 2013.

Fornell D. The development of Renal denervation therapy. Diagnostic and Interventional

Cardiology Magazine, July 30, 2013. http://www.dicardiology.com/article/development-

renal-denervation-therapy. Visited 29-09-2013.

Mahfoud F. Expert consensus document from the European Society of Cardiology on

catheter-based renal denervation. Eur Heart J. 2013a;34(28):2149-57.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

B0003: What is the phase of development and implementation of renal denervation

systems and the treatment alternatives?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

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Dec2013 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 107

Domain search

Other: Google search for each specific RDN system

Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

As the original Symplicity® catheter required multiple ablations, each time requiring the

catheter to be rotated to create a continuous lesion, now the technology is being adapted to

simplify this procedure. St Jude, Covidien and Boston Scientific for example developed new

catheter designs to simplify and shorten the procedure, and also Medtronic itself is develop-

ing a follow-up on the original Symplicity® system.

Of all the renal denervation systems, the Symplicity®, One shotTM

, EnligHTNTM

, Vessix V2TM

-,

and IberisTM

system are CE-marked in Europe. None of the systems are FDA approved, yet all

are in pursuit (Medlatest 2013). Of the ultrasound devices currently under development only

the PARADISETM

system (ReCor Medical) received the CE mark.

Medtronic’s Symplicity® Renal Denervation Device has a several year lead on the other CE-

marked systems, and was accepted for parallel review in the US in March 2013. This program

allows the Centers for Medicare and Medicaid Services (CMS) to begin consideration for

national coverage determination, while the FDA completes its review of safety and efficacy.

The parallel review will be based primarily on results from Symplicity HTN-3 trial. This trial

was expected to conclude in the summer of 2013, and FDA and CMS reviews will likely take

place in 2014 or 2015 (Gaffney 2013).

The Symplicity® renal denervation system is available in more than 70 countries worldwide; it

is only available for investigational use in the U.S. and Japan (Medtronic 2013). Health

Canada issued a Class IV Licence to Medtronic Inc. for the Symplicity® Renal Denervation

System in March 2012.

The Vessix V2TM

system additionally received regulatory approval from the Therapeutic Goods

Authority of Australia and is available for sale in Australia, New Zealand, the Middle East, and

select markets in Asia.

Table 5 shows that in 13 countries in Europe, RDN is reimbursed and in most cases regard-

less of the type of device. Reimbursement is in the majority of countries decided upon

through formal processes, i.e. described in national policy. In one country, Medtronic’s

Symplicity® received conditional coverage. In 5 countries a decision on reimbursement is in

process, 2 countries do not reimburse RDN, and in 3 countries the reimbursement status is

unknown.

Table 5: Reimbursement status of renal denervation in Europe

Country Reimbursement Yes/No Technology-specific vs. non-

technology-specific reimbursement

Austria Yes (temporary, formal) All devices

Belgium - (formal: submissions to the authori-

ties)

All devices

Croatia No -

Denmark Yes (formal) All devices

England - (Commissioning through evaluation;

reimbursement planned to start in

2014)

All devices

Estland - (application under process) Unknown

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Finland Yes (as part of hospital fees) All devices

France - (formal: process waits for STIC re-

sults)

All devices

Germany Yes (formal) All devices

Hungary Unknown Unknown

Greece Unknown Unknown

Italy Yes (formal) All devices

Ireland Yes (decision at local hospital level) All devices

Lithuania Yes (formal) All devices

Malta No -

Netherlands Yes (Conditional Coverage) Currently only Medtronic Symplicity®

Flex

For other technologies, discussion is

on-going

Norway Yes All devices

Poland - (formal: submissions to the authori-

ties)

All devices

Portugal Yes (formal) All devices

Serbia Unknown Unknown

Slovakia Yes (formal) EnligtHTNTM

and Symplicity® reim-

bursed from 01.01.2014

Spain Yes (formal) All devices

Sweden Yes (formal) All devices

Switzerland Yes (formal) All devices

Source: Information on reimbursement status was kindly provided by the EUCOMED Hyper-

tension Working Group and Medtronic. The information has been cross-checked and updated

from WP5 Strand B members. Answers were received from Croatia, England, Finland,

Germany, Hungary, Ireland, Italy, Lithuania, Malta, Poland and Slovakia.

STIC: Support Programme for Innovative and Costly Techniques

Pharmacological Therapy

Several new pharmacological therapies for hypertension are being investigated in phase 2

and 3 clinical trials including drugs with new pharmacological targets (such as dual vasopep-

tidase inhibitors, a dual-acting angiotensin receptorneprilysin inhibitor, endothelin antago-

nists, nitric oxide donors, and angiotensin vaccines) and novel, fixed-dose combination drug

products (CADTH 2013).

Discussion

Although BP has been the primary outcome variable in the studies, there are several reports

that suggest beneficial effects also in patients with diabetes mellitus, metabolic syndrome,

cardiac arrhythmias, sleep apnea and heart failure. In the U.S. it is foreseen that once RDN

systems gain FDA market approval, physicians will begin using them off-label for conditions

other than hypertension (Fornell 2013). In Europe indication widening may also become an

issue that, as here the devices are only CE-marked, and not fixed to a certain indication.

References

CADTH. Catheter-based renal denervation fortreatment-resistant hypertension. Issues in

emerging Health Technologies CADTH issue 121, March 2013.

Fornell D. The development of Renal denervation therapy. Diagnostic and Interventional

Cardiology Magazine, July 30, 2013. http://www.dicardiology.com/article/development-

renal-denervation-therapy. Visited 29-09-2013.

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Dec2013 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 109

Medlatest. Renal Denervation: Just How Big Is The Bandwagon? June 18, 2013.

http://www.medlatest.com/2012/06/18/renal-denervation-just-how-big-is-the-bandwagon/

accessed 12.09.13.)

Medtronic. 25 may 2013. http://newsroom.medtronic.com/phoenix.zhtml?c=251324&p=irol-

newsArticle&id=1823583 visited 12.09.13).

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely however the information needs to be updated regularly

Partly

Not

B0004: Who performs or administers renal denervation and the treatment alternatives?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

Domain search

Other:

Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

RDN can be performed in a catheterization laboratory, for cardiovascular interventions

(Andersson 2013; CADTH 2013). The procedure can be performed by interventional

cardiologists, or – radiologist, and angiologists. The European Society of Cardiology recom-

mends that the procedure is performed by staff that has been trained in performing this

intervention, and who are qualified to manage potential complications, such as acute

dissection of renal arteries by stent implantation. The procedure is performed under

analgesic or conscious sedation (CADTH 2013). During the procedure, vital signs need to be

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monitored. The presence of an anaesthesiologist is not generally necessary, however in some

countries required (Mahfoud 2013a).

Discussion

-

References

Andersson B, Herlitz H, Manhem K, Zachrisson K, VöLz S, Daxberg EL, et al. Renal sympathet-

ic denervation in patients with therapy resistant hypertension.: The Regional Health Technol-

ogy Assessment Centre (HTA-centrum), Region Vastra Gotaland; 2013

CADTH. Catheter-based renal denervation for treatment-resistant hypertension. Issues in

emerging Health Technologies CADTH issue 121, March 2013.

Mahfoud F. Expert consensus document from the European Society of Cardiology on

catheter-based renal denervation. Eur Heart J. 2013a;34(28):2149-57.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

B0005: In what context and level of care are renal denervation systems and the

treatment alternatives used?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

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Domain search

Other:

Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

Andersson et al. recommend that in the selection of patients, primary care physicians and

specialist in internal medicine, nephrology, interventional cardiology or radiology should be

involved (Andersson 2013). Appropriate expertise can be assumed in centres with >25 renal

interventions per year.

The long term follow-up of RDN treated patients is similar to usual care of hypertensive

patients. It can be done by specialists in cardiology, internal medicine or nephrology, as well

as primary care physicians (Andersson 2013).

Discussion

-

References

Andersson B, Herlitz H, Manhem K, Zachrisson K, VöLz S, Daxberg EL, et al. Renal sympathet-

ic denervation in patients with therapy resistant hypertension.: The Regional Health Technol-

ogy Assessment Centre (HTA-centrum), Region Vastra Gotaland; 2013

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

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B0008: What kind of special premises are needed to use renal denervation systems and

treatment alternatives?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

Domain search

Other:

Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

See B0005

Discussion

-

References

-

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

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B0009: What materials are needed to use renal denervation systems and the treatment

alternatives?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

Domain search

Other:

Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

There will be a slight increase in the demand for functional and morphological diagnostic

protocol prior to RDN (Andersson 2013). In the CADTH assessment it is concluded that RDN

is associated with additional health care resources in terms of the cost of the system, the

training of specialist staff, and the use of hospital radiology services during the procedure,

as RDN is currently used as an adjunct to available therapies for hypertension (CADTH 2013).

Discussion

-

References

Andersson B, Herlitz H, Manhem K, Zachrisson K, Völz S, Daxberg EL, et al. Renal sympathet-

ic denervation in patients with therapy resistant hypertension: The Regional Health Technol-

ogy Assessment Centre (HTA-centrum), Region Vastra Gotaland; 2013

CADTH. Catheter-based renal denervation for treatment-resistant hypertension. Issues in

emerging Health Technologies CADTH issue 121, March 2013.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

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Dec2013 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 114

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

B0010: What kind of data and records are needed to monitor the renal denervation

systems and the treatment alternatives?

Methods

See B0011

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

Domain search

Other:

Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

See B0011

Discussion

-

References

-

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

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How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

B0011: What kind of registry is needed to monitor the use renal denervation systems

and treatment alternatives?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

Domain search

Other: Google search: renal denervation and registry

Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

The Joint UK Societies consensus statement on RDN for resistant hypertension (Caulfield

2012) states that any institution carrying out the procedure should have the commitment

and capability to include data in a National Registry. This will allow for analysis of the

procedural success acutely and at long-term follow-up (Mahfoud 2013a).

Discussion

In the case of indication-widening registries would have to be set up for each indication.

References

Caulfield M, De Belder M, Cleveland

T, Collier D, Deanfield J, Gray

H, Knight C, Lobo M,

Matson M, Moss J, Simpson

I, Tomson C, Williams B. The Joint UK Societies’ Consensus

Statement on Renal Denervation for Resistant Hypertension. January 2012.

http://www.bhsoc.org/docs/The-Joint-UK-Societies'-Consensus-on-Renal-Denervation-for-

resistant-hypertension.pdf

Mahfoud F. Luscher TF, Andersson B, Baumgartner I, Cifkova R, DiMario C et al. Expert

consensus document from the European Society of Cardiology on catheter-based renal

denervation. Eur Heart J. 2013a;34(28):2149-57.

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Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as

such?

Completely

Partly

Not

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Safety

C0001: What are the adverse events and serious adverse events in patients treated with

renal denervation?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

Domain search

Other:

Critical appraisal criteria: Cochrane risk of bias tool.

Method of synthesis: GRADE

Result

The evidence for the safety domain comes from three RCT articles, three non-RCT articles and

16 case series studies reporting on 904 patients. For 91 patients information could be partly

duplicated. Twenty-six patients of the Mahfoud study (Mahfoud 2011b), 28 patients of the

Ukena study from 2011 (Ukena 2011) and 18 of the Ukena study from 2012 (Ukena 2012)

were part of the Symplicity HTN-2 trial (Symplicity HTN-2 2010; Esler 2012) and 19 patients

of the Mahfoud study (Mahfoud 2012) were included in the Symplicity HTN-1 or Symplicity

HTN-2 trials.

In two of the three RCTarticles, all of the non-RCT studies and 11 of the 16 cases series, the

RDN procedure involved radiofrequency ablation (RF) applied with the Symplicity® catheter

(Medtronic, Ardian Inc). A total of 784 patients underwent RDN using this system. One RCT

including 13 patients carried out the intervention using a Navistar®

ThermoCool® Irrigated Tip

Catheter (Biosense Webster) (Pokushalov 2012). One case series with 30 patients used the

Marinr® RF ablation catheter (typically used for cardiac ablation) (Prochnau 2012a), one with

46 patients used the EnligHTN® multi-electrode renal denervation system (EnligHTN1 trial)

(Worthley 2013) and one with 9 patients used the OneShot™ (Covidien) RDN system (RHAS

trial) (Ormiston 2013). One case series with 11 patients carried out RDN with the Paradise™

technology (ReCor Medical), which uses a catheter that emits ultrasound energy (Mabin 2012)

and one with 11 patients did not specify the type of system used (Voskuil 2011).

Overall, out of the 22 studies, thirteen reported procedure-related complications (Symplicity

HTN-2 2010, Mahfoud 2011b; Mahfoud 2012; Symplicity HTN-1 2011; Esler 2012; Mabin

2012; Ukena 2012; Vase 2012; Fontenla 2013; Kaltenbach 2013; Ormiston 2013; Scheurig-

Muenkler 2013; Worthley 2013). The pooling of these studies to estimate frequencies of

complications was not possible due to the high risk of selective outcome reporting.

Reported adverse events related to the procedure or device

Even though not quantified in the majority of studies as an adverse event, it is documented

that RDN frequently causes ‘diffuse visceral abdominal pain’ during the procedure that can

be adequately controlled with narcotics or anaesthesics (Mahfoud 2011b; Symplicity HTN-1

2011; Hering 2012; Mabin 2012; Prochnau 2012a; Simonetti 2012; Vase, 2012; Fontenla

2013; Worthley 2013). The most commonly reported procedure or device related complica-

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tions were of a mild to moderate nature: hypotensive episodes (1.92%-55.5%) (Symplicity

HTN-2 2010; Esler 2012; Vase 2012; Worthley 2013), femoral artery pseudoaneu-

rysms/hematomas at the access site (1.5 % - 44.4 %) (Symplicity HTN-2 2010; Mahfoud

2011b; Mahfoud 2012; Symplicity HTN-1 2011; Ukena 2012, Fontenla 2013; Ormiston 2013;

Worthley 2013 ), bradychardias (4.35 % -18 %) (Symplicity HTN-2 2010; Symplicity HTN-1

2011; Fontenla 2013; Worthley 2013), , renal artery spasms series (5 % - 26 %) (Vase 2012;

Kaltenbach 2013; Worthley 2013), transient vagal reactions (3.9 % -11.1 %) (Symplicity HTN-1

2011, Ukena 2012; Ormiston 2013; Worthley 2013;) and vomiting (2.17 % - 11.1 %) (Ormiston

2013; Worthley 2013). Other minor periprocedural events notified in isolated studies were:

haematuria (4.35 %) (Worthley 2013), dizziness (3.92 %) (Symplicity HTN-1 2011), urine infec-

tions (Symplicity HTN-2 2010), paraesthesias (1.92 %) (Symplicity HTN-2 2010), and contrast

medium allergic reactions (1.14 %) (Mahfoud 2012). Several studies denoted the appearance

of minor focal renal artery irregularities not flow limiting attributed to minor spasm and/or

edema but these were not counted as complications (Symplicity HTN-1 2011; Mabin 2012;

Prochnau 2012a; Simonetti 2012; Scheurig-Muenkler 2013).

Major complications related to the procedure or the device were reported in four studies.

Three studies accounted for renal artery dissection on placement of catheter (0.65 % - 9.9%)

(Symplicity HTN-1 2011; Esler 2012; Mabin 2012), one study reports a psoas hematoma sec-

ondary to placement of catheter (9.09%) (Fontenla 2013) and one study describes one case of

respiratory and cardiocirculatory depression due to analgosedation (1,89 %) and one case of

severe artery spasm that resulted in residual stenosis of no hemodynamic relevance (1,89 %)

(Scheurig-Muenkler 2013).. No intervention-related mortality has been reported.

The frequency of complications related to the procedure notified in the included studies are

outlined in the table below.

Frequency of main procedure or device related complications reported in the included studies

Follow up adverse events

Nine studies (Symplicity HTN-1 2011; Symplicity HTN-2 2010; Mahfoud 2011b; Mahfoud

2012; Brinkmann 2012; Esler 2012; Mabin 2012; Kaltenbach 2013; Worthley 2013) docu-

mented complications during the follow up period (maximum of 2 years).

The most common minor complication was the lowering of blood levels below target BP or

the development of hypotensive symptoms (18.2%-35.1%) (Mahfoud 2011b, Mahfoud 2012,

Mabin 2012). Other minor complications include edemas (1.92 % - 5 %) (Symplicity HTN-1

2011; Symplicity HTN-2 2010; Kaltenbach 2013 ) and flank pain (2.6 %) (Symplicity HTN-1

2011)

Six studies reported major adverse events during follow (n=315 patients) (Symplicity HTN-2

2010; Esler 2012; Brinkmann 2012, Kaltehbach 2013, Worthey 2013). The documented fre-

quency of complications were: hypertensive emergencies and crisis (5%- 33.3 %) (Symplicity

HTN-2 2010; Esler 2012; Brinkmann 2012; Kaltenbach 2013); hypotensive events requiring

hospitalization (2% - 2.86 %) (Symplicity HTN-2 2010; Esler 2012; Worthley 2013), angina

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(2.04 %) (Symplicity HTN-2 2010), transient ischaemic attacks (2.04 %) (Symplicity HTN-2

2010), progression of existing stenosis (0.65%-2.17%) (Symplicity HTN-2 2010; Symplicity

HTN-1 2011; Worthley 2013), and hypertensive renal disease progression: (2.17 %) (Worthley

2013). None of the studies reported aortic stenosis, thrombosis or important abnormalities.

The frequency of follow up complications notified in the included studies are outlined in the

table below.

Frequency of main procedure or device related complications reported in the included studies

The quality of the evidence was low or very low. The table below shows the Grade profile for

total adverse events and major adverse events.

Evidence profile for total and major adverse events

Discussion

The reporting frequency of adverse events was very heterogeneous (0 % - 40.38 %) in the in-

cluded studies and this raises important uncertainties regarding the overall rate of complica-

tions. In two of the RCT studies (Ukena 2011; Pokushalov 2012), all of the non RCT studies

(Mahfoud 2011b; Mahfoud 2012; Brandt 2012a) and many of the case series safety was not

considered the main endpoint and complications and adverse events were reported incom-

pletely (Voskuil 2011; Brinkmann 2012; Hering 2012; Ukena 2012; Zuern 2012; Prochnau

2012a; Fontenla 2013; Kaltehbach 2013). Often authors only make reference to the non ex-

istence of major/severe complications or adverse events related to the procedure without

defining what was meant with severe adverse event, or commenting on post-procedure ad-

verse events, which hampers the interpretation of evidence related to safety, making it im-

possible to perform pooled analysis of data.. One of the main complications of RDN are the

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unwanted effects with respect to BP regulation post procedure, which can derive in hypoten-

sion or hypertension episodes that can require hospitalization. It cannot be dismissed that

these or other indirect complications, such as the appearance of respiratory and cardiocircu-

latory depression related to the control of analgesia and sedation mentioned in the study of

Scheurig-Muenkler (Scheurig-Muenkler 2012) are underestimated in the included studies.

The follow-up time was inadequate to analyze long term complications. Renal function con-

cerns and doubts as to the aggravation of renal disease are still to be resolved (Mahfoud

2011b; Mahfoud 2012). The Symplicity HTN-2 investigations and several other trials that ana-

lyzed renal function (Symplicity HTN-2 2010; Esler 2012; Pokushalov 2012; Mahfoud 2011b;

Mahfoud 2012; Prochnau 2012a; Fontenla 2013; Kaltenbach 2013; Ormiston 2013) observed

no changes in estimated glomerular filtration rate (eGFR), cystatin C or other parameters

used to detect renal failure function in the 3-12 months’ follow-up period. However, in the

Symplicity HTN-1 trial with extended follow-up of 24 months, estimated GFR remained stable

within the first years, but in 10 patients followed 2 years a dramatic decrease in the eGFR rate

was observed. Whether these differences might be attributed to different study population,

differences in BP levels or the detrimental effect of renal denervation requires clarification.

For this purpose, longer term assessments are needed.

There is uncertainty regarding the detrimental effect on the anatomy of the renal arteries

with this invasive procedure. Mild, hemodynamically irrelevant wall irregularities correspond-

ing to small local spasms or circumscribed wall edema were consistently seen after ablation,

but these were not flow limiting. Several of the included studies (Esler 2012; Pokushalov

2012; Mahfoud 2011b; Mahfoud 2012; Symplicity HTN-1 2011; Prochnau 2012a; Fontenla

2013; Kaltenbach 2013) carried out a magnetic resonance angiography, computed tomo-

graphic scan and or renal ultrasound during the follow up period and ruled out the appear-

ance of renal artery aneurisms, stenosis, thrombosis or any other relevant vascular abnormal-

ities in the short to medium term (6-12 months) but the evolution of the renal arteries in the

long term is unknown.

Current RDN experiences are mainly based on the Symplicity® catheter (Medtronic, Ardian,

Inc). The other RDN systems and new generations of RDN systems have only been assessed in

preliminary trials that include very few patients. Since these systems do not use exactly the

same ablation mechanisms and the diameter of the catheter can be different, it cannot be

dismissed that they could present a different risk profile. These systems require further as-

sessment to establish their safety.

In summary, evidence about safety is compromised by the following methodological limita-

tions that impede drawing up definitive conclusions about this procedure:

The majority of studies present a small sample size and many an overlap of patients.

Safety is not the primary end point in the vast majority of studies and complications

are incompletely recorded

In many of the studies, the RD intervention was conducted in highly selected patients

by a small group of trained health professionals, which does not exclude the possibil-

ity of serious adverse effects if the technique is performed routinely in clinical prac-

tice.

Possibility of bias due to lack of blinding.

Large heterogeneity in individual responses to renal sympathetic ablation.

Short follow-up, which means that there is a lack of knowledge about long-term po-

tential of nerve fiber regeneration and the occurrence of adverse effects.

Potential conflicts of interest in most of the included studies because of their financ-

ing from the manufacturer of the device and / or participation in research studies of

company’s invetigators (see evidence tables in Annex 1).

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References

Brandt MC, Reda S, Mahfoud F, Lenski M, Bohm M, Hoppe UC. Effects of renal sympathetic

denervation on arterial stiffness and central hemodynamics in patients with resistant

hypertension. J Am Coll Cardiol. 2012a;60(19):1956-65.

Brinkmann J, Heusser K, Schmidt BM, Menne J, Klein G, Bauersachs J, et al. Catheter-based

renal nerve ablation and centrally generated sympathetic activity in difficult-to-control

hypertensive patients: prospective case series. Hypertension. 2012;60(6):1485-90.

Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic

denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a

randomised controlled trial. Lancet. 2010;376(9756):1903-9.

Esler MD, Krum H, Schlaich M, Schmieder RE, Bohm M, Sobotka PA. Renal sympathetic

denervation for treatment of drug-resistant hypertension: one-year results from the

Symplicity HTN-2 randomized, controlled trial. Circulation. 2012;126(25):2976-82.

Fontenla A, Garcia-Donaire JA, Hernandez F, Segura J, Salgado R, Cerezo C, et al. Management

of resistant hypertension in a multidisciplinary unit of renal denervation: protocol and results.

Rev Esp Cardiol. 2013;66(5):364-70.

Hering D, Mahfoud F, Walton AS, Krum H, Lambert GW, Lambert EA, et al. Renal denervation

in moderate to severe CKD. J Am Soc Nephrol. 2012;23(7):1250-7.

Kaltenbach B, Franke J, Bertog SC, Steinberg DH, Hofmann I, Sievert H. Renal sympathetic

denervation as second-line therapy in mild resistant hypertension: a pilot study. Catheter

Cardiovasc Interv. 2013;81(2):335-9.

Mabin T, Sapoval M, Cabane V, Stemmett J, Iyer M. First experience with endovascular

ultrasound renal denervation for the treatment of resistant hypertension. EuroIntervention.

2012;8(1):57-61.

Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, et al. Effect of renal

sympathetic denervation on glucose metabolism in patients with resistant hypertension: a

pilot study. Circulation. 2011b;123(18):1940-6.

Mahfoud F, Cremers B, Janker J, Link B, Vonend O, Ukena C, et al. Renal hemodynamics and

renal function after catheter-based renal sympathetic denervation in patients with resistant

hypertension. Hypertension. 2012;60(2):419-24.

Ormiston JA, Watson T, van Pelt N, Stewart R, Stewart JT, White JM, et al. Renal denervation for

resistant hypertension using an irrigated radiofrequency balloon: 12-month results from the

Renal Hypertension Ablation System (RHAS) trial. EuroIntervention. 2013;9(1):70-4.

Pokushalov E, Romanov A, Corbucci G, Artyomenko S, Baranova V, Turov A, et al. A

randomized comparison of pulmonary vein isolation with versus without concomitant renal

artery denervation in patients with refractory symptomatic atrial fibrillation and resistant

hypertension. J Am Coll Cardiol. 2012 Sep 25;60(13):1163-70.

Prochnau D, Figulla HR, Surber R. Efficacy of renal denervation with a standard EP catheter in

the 24-h ambulatory blood pressure monitoring-long-term follow-up. Int J Cardiol.

2012a;157(3):447-8.

Scheurig-Muenkler C, Weiss W, Foert E, Toelle M, van der Giet M, Kroncke TJ, et al. Renal

denervation for refractory hypertension - technical aspects, complications and radiation

exposure. Rofo. 2013;185(6):550-7.

Simonetti G, Spinelli A, Gandini R, Da Ros V, Gaspari E, Coco I, et al. Endovascular

radiofrequency renal denervation in treating refractory arterial hypertension: a preliminary

experience. Radiol Med. 2012;117(3):426-44.

Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant

hypertension: durability of blood pressure reduction out to 24 months. Hypertension.

2011;57(5):911-7.

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Dec2013 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 122

Ukena C, Mahfoud F, Spies A, Kindermann I, Linz D, Cremers B, et al. Effects of renal

sympathetic denervation on heart rate and atrioventricular conduction in patients with

resistant hypertension. Int J Cardiol. 2012 Aug 20.

Vase H, Mathiassen ON, Kaltoft A, Pedersen EB, Christensen KL, Buus NH, et al. Catheter-

based renal denervation for treatment of resistant hypertension. Dan Med J.

2012;59(6):A4439.

Voskuil M, Verloop WL, Blankestijn PJ, Agostoni P, Stella PR, Doevendans PA. Percutaneous

renal denervation for the treatment of resistant essential hypertension; the first Dutch

experience. Neth Heart J. 2011;19(7-8):319-23.

Worthley SG, Tsioufis CP, Worthley MI, Sinhal A, Chew DP, Meredith IT, et al. Safety and

efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension:

the EnligHTN I trial. Eur Heart J. 2013;34(28):2132-40.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

C0002: Are there any dose relationship of the harms (e.g. intensity, length of treat-

ment)?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

Domain search

Other:

Critical appraisal criteria: Cochrane risk of bias tool.

Method of synthesis: GRADE

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Result

This question can not be answered with the available evidence.

Discussion

-

References

-

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

C0004: What are the potential short- and long term harms, their frequency, and differ-

ences according to settings?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

Domain search

Other:

Critical appraisal criteria: Cochrane risk of bias tool.

Method of synthesis: GRADE

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Result

There is no evidence to establish if the safety profile of the technology varies between differ-

ent RDN systems or organizational settings.

Discussion

-

References

-

Importance and transferability

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Critical

Important

Optional

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Completely

Partly

Not

C0005: Are there any susceptible patient groups more likely to be harmed?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

Domain search

Other:

Critical appraisal criteria: Cochrane risk of bias tool.

Method of synthesis: GRADE

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Result

Patients with chronic renal disease could be more susceptible to RDN harm. All initial RCTs

and other included studies restrict inclusion criteria to patients that have an estimated GFR

(eGFR) ≤45 ml/min per 1.73 m2

. Only one of the included studies (Hering 2012) evaluates

patients with moderate to severe renal disease (stage 3-4). This study finds no significant

alteration in renal function as assessed by estimation of GFR according to serumcreatinine or

cystatin C levels and according to plasma creatinine, cystatin C, or urea. Scheurig-Muenkler et

al. reports that two patients with end stage renal disease and one patient with chronic renal

failure that received RDN in their study did not exhibit any worsening in renal function

(Scheurig-Muenkler 2013). In the series presented by Prochnau et al. serum creatinine and

proteinura, used as markers of renal function, remains unchanged in four patients with

chronic renal insufficiency (Prochnau 2012a).

Discussion

Renal function concerns and doubts as to the aggravation of renal disease are still to be re-

solved (Mahfoud 2011b; Mahfoud 2012). Information is limited regarding the use of renal

denervation in patients with impaired renal function and long term assessments are needed.

The main limitation observed in great majority of initial randomised clinical trials and other

included studies is that patients have an estimated GFR (eGFR) ≤45 ml/min per 1.73 m2

) and

present preserved renal function. The study of Hering et al. suggests that the renal function

remains unaltered in patients with moderate to severe renal disease (stage 3-4) but this study

is limited by the design (case series) and small number of patients. It should be clarified in

further studies whether these patients are candidates for RDN.

References

Hering D, Mahfoud F, Walton AS, Krum H, Lambert GW, Lambert EA, et al. Renal denervation

in moderate to severe CKD. J Am Soc Nephrol. 2012;23(7):1250-7.

Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, et al. Effect of renal

sympathetic denervation on glucose metabolism in patients with resistant hypertension: a

pilot study. Circulation. 2011b;123(18):1940-6.

Mahfoud F, Cremers B, Janker J, Link B, Vonend O, Ukena C, et al. Renal hemodynamics and

renal function after catheter-based renal sympathetic denervation in patients with resistant

hypertension. Hypertension. 2012;60(2):419-24.

Prochnau D, Figulla HR, Surber R. Efficacy of renal denervation with a standard EP catheter in

the 24-h ambulatory blood pressure monitoring-long-term follow-up. Int J Cardiol.

2012a;157(3):447-8.

Scheurig-Muenkler C, Weiss W, Foert E, Toelle M, van der Giet M, Kroncke TJ, et al. Renal

denervation for refractory hypertension - technical aspects, complications and radiation

exposure. Rofo. 2013;185(6):550-7.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

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How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

C0007: Can adverse events be caused by the behaviour of patients, professionals or

manufacturers?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

Domain search

Other:

Critical appraisal criteria: Cochrane risk of bias tool.

Method of synthesis: GRADE

Result

This question can not be answered with the available evidence. However, based on the tech-

nical requirements it is reasonable to assume that procedure-related complications might

depend on professional experience.

Discussion

In many of the studies, the RDN intervention was conducted in highly selected patients by a

small group of trained health professionals, which does not exclude the possibility of major

adverse effects if the technique is to be performed routinely in clinical practice.

References

-

Importance and transferability

How important is this piece of information for decision making?

Critical

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Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

C0008: What is the safety of renal denervation in relation to standard of care (which

includes additional pharmacological treatment, device based therapy of hypertension

and sham treatment)?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information:

Basic documentation

Domain search

Other:

Critical appraisal criteria: Cochrane risk of bias tool.

Method of synthesis: GRADE

Result

The Symplicity HTN-2 RCT (Symplicity HTN-2 2010) reported that 40.3% of the patients (n=

21) treated with RF ablation suffered minor and major complications with respect to 9.26 % of

the patients (n=5) that received only pharmacological medications. The majority of adverse

events in the RDN group were related to the procedure or device. During the 6 months follow

up period major complications appeared in 16.3 % (n=8) and 9.8 % (n=5) of the patients, re-

spectively (Table below). One RDN patient and 2 control patients suffered a transient ischem-

ic attack and one patient from each group an angina. Additional serious events requiring

hospitalization among patients who underwent RDN, included one case nausea and oedema

(n=1), one hypotensive episode (n=1) three hypertensive emergencies unrelated to non per-

sistence with drugs and one hypertensive crisis after stopping clonidine. Two control groups

presented hypertensive emergencies. Renal function, as assessed by serum creatinine, eGFR,

and cystatin C concentrations were unchanged from baseline in both groups at 6 months.

In the extension of the Symplicity HTN2-trial (Ukena 2011) authors declare that RD was per-

formed without any major adverse events in all patients (37 interventions and 9 controls) but

do not provide results on overall complications. The publication of Mahfoud from 2011 (Mah-

foud 2011b) reports that one patient from the RDN treated group (n=37) developed a pseu-

doaneurysm of the femoral artery site (2.7%) and after 3 months, 13 patients experienced

hypotension associated with symptoms (35%). Two patients that received only pharmacologi-

cal medication (n=13) presented signs or symptoms consistent with hypertension (15.4%). In

the 2012 publication (Mahfoud 2012) it is stated that the RDN procedure was performed

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without any complication in 97% of the patients (n=110). Two patients developed a pseudo-

aneurysm of the femoral artery site (2.27%) and one experienced a contrast medium allergic

reaction (1.14%). During the 6 months follow up period antihypertensive drug regimens had

to be reduced in 18 treated patients (18%) and increased in 7 due to development of symp-

toms. The mean cystatin C glomerular filtration rate and urinary albumin excretion remained

unchanged after RDN in all of the studies. No abnormalities of the renal arteries (significant

artery stenosis or aneurysms) were observed during the study period.

In the RCT that assessed the impact of renal artery denervation (Navistar®

ThermoCool®

cathe-

ter) added to PVI in respect to carrying out only PVI, no acute adverse events or renal artery

stenosis were reported in either group at 6 months; the manuscript does not comment on

other post-procedural adverse events (Pokushalov 2012).

Reported follow up complications in included trials

The overall quality of the evidence is low (Table below). The incompletely recording of ad-

verse events in included studies makes impossible pooling data to estimate frequencies of

adverse events.

Evidence profiles for total and major adverse events

Discussion

As it may be anticipated, RDN patients present procedure related complications that are not

seen in pharmacological treated patients but the majority are mild-moderate in nature and

can be successfully controlled.

Since safety was not the main endpoint in four of the five included trials (Ukena 2011;

Pokushalov 2012; Mahfoud 2011b; 2012; Brandt 2012a), post-procedural complications are

incompletely reported. Results suggest that RDN treated patients could have more problems

with the regulation of their BP, which could result in more hospital admissions due to hypo-

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tensive and hypertensive emergencies. However, this is to be confirmed in trials adequately

designed. With the available evidence it is impossible to make any conclusion with respect to

the frequency of follow up complications.

The follow up time was inadequate to analyze long term complications. Renal function con-

cerns and doubts as to the aggravation of renal disease are still to be resolved (Mahfoud

2011b; Mahfoud 2012). The included trials did not observe changes in estimated glomerular

filtration rate (eGFR), cystatin C or other parameters used to detect renal failure function in

the 3-12 months’ follow-up period. However, in the Symplicity HTN-1 trial with extended fol-

low-up of 24 months, estimated GFR remained stable within the first years, but in 10 patients

followed 2 years a dramatic decrease in the eGFR rate was observed. Whether these differ-

ences might be attributed to different study population, differences in BP levels or the detri-

mental effect of renal denervation requires clarification. For this purpose, longer term as-

sessments are needed.

There is uncertainty regarding the detrimental effect on the anatomy of the renal arteries

with this invasive procedure. Mild, hemodynamically irrelevant wall irregularities correspond-

ing to small local spasms or circumscribed wall oedema were consistently seen after RDN,

but did not limit blood flow. Several of the included trials (Symplicity HTN-2 2010;

Pokushalov 2012; Mahfoud 2011b; Mahfoud 2012) carried out a magnetic resonance angi-

ography, computed tomographic scan and/or renal ultrasound during the follow-up period

and ruled out the appearance of renal artery aneurisms, stenosis, thrombosis or any other

relevant vascular abnormalities in the short to medium term (6-12 months), but the evolution

of the renal arteries in the long term is unknown.

References

Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic

denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a

randomised controlled trial. Lancet. 2010;376(9756):1903-9.

Esler MD, Krum H, Schlaich M, Schmieder RE, Bohm M, Sobotka PA. Renal sympathetic

denervation for treatment of drug-resistant hypertension: one-year results from the

Symplicity HTN-2 randomized, controlled trial. Circulation. 2012;126(25):2976-82.

Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, et al. Effect of renal

sympathetic denervation on glucose metabolism in patients with resistant hypertension: a

pilot study. Circulation. 2011b;123(18):1940-6.

Mahfoud F, Cremers B, Janker J, Link B, Vonend O, Ukena C, et al. Renal hemodynamics and

renal function after catheter-based renal sympathetic denervation in patients with resistant

hypertension. Hypertension. 2012;60(2):419-24.

Pokushalov E, Romanov A, Corbucci G, Artyomenko S, Baranova V, Turov A, et al. A

randomized comparison of pulmonary vein isolation with versus without concomitant renal

artery denervation in patients with refractory symptomatic atrial fibrillation and resistant

hypertension. J Am Coll Cardiol. 2012;60(13):1163-70.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

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Completely

Partly

Not

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Clinical Effectiveness

D0001: What is the effect of renal denervation on overall mortality?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information: Davis 2013 (SR)

Basic documentation

Domain search

Other:

Critical appraisal criteria: NOKC check-list for systematic reviews

Method of synthesis: narrative (GRADE not applicable)

Result

According to Davis and colleagues, no deaths were reported during the stipulated follow-up

periods (Davis 2013).

Discussion

No conclusion can be drawn from the evidence available. None of the ongoing studies identi-

fied in this rapid assessment listed mortality as their main research questions.

References

Davis MI, Filion KB, Zhang D, Eisenberg MJ, Afilalo J, Schiffrin EL, Joyal D. Effectiveness of re-

nal denervation therapy for resistant hypertension: a systematic review and meta-analysis. J

Am Coll Cardiol 2013;62(3):231-241.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

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D0002: What is the effect of renal denervation on cardiovascular mortality?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information: No SR or RCT or non-RCT (i.e. prospective controlled trial) found

Basic documentation

Domain search

Other:

Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

None of the identified publications in this rapid assessment have addressed cardiovascular

mortality.

Since no mortality was reported in the identified publications, one can extrapolate that there

has been no cardiovascular mortality either.

Discussion

Since none of the identified studies in this rapid assessment have addressed cardiovascular

mortality, no conclusion can be drawn. None of the ongoing studies identified in this rapid

assessment are assessing this research question as their main focus.

References

-

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

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D0005: How does renal denervation affect symptoms and findings?

Cardiovascular morbidity: (stroke, myocardial infarction, heart failure)

Left ventricular hypertrophy

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information: for cardiovascular morbidity in terms of stroke, myocardial infarction,

heart failure: Andersson 2013 (SR), and for left ventricular hypertrophy: Andersson 2013 (SR),

Mahfoud 2013b (non-RCT, i.e. prospective controlled trial) and Pokushalov 2012 (RCT)

Basic documentation

Domain search

Other:

Critical appraisal criteria: NOKC check-list for systematic reviews and Cochrane risk of bias

checklist for RCTs

Method of synthesis: GRADE for the outcome left ventricular hypertrophy (GRADE was not

applicable for cardiovascular morbidity)

Result

Cardiovascular morbidity

The SR by Andersson et al. was the only SR having assessed cardiovascular morbidity in

terms of stroke, myocardial infarction and/or heart failure (Andersson 2013), but found no

studies. Among the RCT and non-RCTs (prospective controlled trials) we identified none that

had assessed this outcome.

Change in left ventricular mass (for left ventricular hypertrophy)

The SR by Andersson et al. included one non-RCT which assessed left ventricular hypertrophy

in 64 patients (46 in the intervention group and 18 in the control group) 6 months following

renal denervation using the Symplicity® system (Brandt 2012b). The mean difference in left

ventricular mass (grams) per body surface (square meters) was 23.8 g/m2

. This result was

significant in favor of renal denervation, but the quality of this evidence was very low (Table

EFF1).

One non-RCT (prospective controlled trial) with 46 patients (37 in the intervention group and

9 in the control group) assessed left ventricular hypertrophy also 6 months after renal dener-

vation using Symplicity® (Mahfoud 2013b), but measured left ventricular mass (grams) in-

dexed to height 1.7 meter. The mean difference between the two groups was 3.6 g/m1.7

and

not significant. The quality of this evidence was very low (Table EFF1).

One RCT with 27 patients (13 in the intervention group and 14 in the control group) also as-

sessed left ventricular hypertrophy after 6 months, but used the Navistar® ThermoCool® sys-

tem (Pokushalov 2012). The left ventricular mass index measured in g/m (calculation formula

was not indicated) was 15.4 g/m lower in the patients who had undergone renal denervation.

The mean difference which was significant, but the quality this evidence was very low (Table

EFF 1).

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Table EFF1: Difference in left ventricular mass

Quality assessment No of patients Effect

Quality Importance

No of studies

Design Risk of bias

Inconsistency Indirectness Imprecision Other consider-ations

Renal denervation

Control Relative (95% CI)

Absolute

LV hypertrophy - Symplicity - LV mass post treatment at 6 months (measured with: LV mass/body surface area (g/m2); better indicated by lower values)

1 non-RCT

no serious risk of bias

2

no serious inconsistency

no serious indirectness

very seri-ous

1,3

none 46 18 - MD 23.8 lower (40.16 to 7.44 lower)

VERY LOW

IMPORTANT

LV hypertrophy - Symplicity - LV mass post treatment at 6 months (measured with: LV mass indexed to height 1.7 (g/m1.7); better indicated by lower values)

1 non-RCT

no serious risk of bias

2

no serious inconsistency

no serious indirectness

very seri-ous

1,3

none 37 9 - MD 3.6 higher (3.57 lower to 10.77 higher)

VERY LOW

IMPORTANT

LV hypertrophy – Navistar ThermoCool- LV mass change at 6 months (measured with: LVMI (g/m); better indicated by lower values)

1 RCT no serious risk of bias

no serious inconsistency

serious4 very seri-

ous1,3

none 13 14 - MD 15.4 lower

(20.05 to 10.75 lower)

VERY LOW

IMPORTANT

1

Few participants (GRADE give suggested recommendation for imprecision : total population size is less than 400 (a threshold rule-of-thumb value; using

the usual α and β, and an effect size of 0.2 SD, representing a small effect)

2

Controlled but not randomized trial.

3

Only one study, unknown reproducibility

4

Tested pulmonary vein isolation +/- renal denervation. Participants had atrial fibrillation in addition to treatment-resistant hypertension.

Discussion

Although two out of three studies showed less left ventricular hypertrophy in patients having

undergone renal denervation using Symplicity® and Navistar® ThermoCool® systems com-

pared with patients who had not, study sizes were small, left ventricular mass was measured

differently and different study designs were used. The poor quality of the evidence does not

allow for drawing any definite conclusions.

None of the ongoing studies identified in this rapid assessment are assessing this research

question as their primary objective.

References

Andersson B, Herlitz H, Manhem K, Zachrisson K, Völz S, Daxberg EL, et al. Renal sympathetic

denervation in patients with therapy resistant hypertension: The Regional Health Technology

Assessment Centre (HTA-centrum), Region Vastra Gotaland; 2013.

Brandt MC, Mahfoud F, Reda S, Schirmer SH, Erdmann E, Böhm M, Hoppe UC. Renal sympa-

thetic denervation reduces left ventricular hypertrophy and improves cardiac function in pa-

tients with resistant hypertension. J Am Coll Cardiol 2012b;59(10):901-9.

Mahfoud F, Urban D, Teller DC, Ukena C, Fries P, Schneider G, et al. Renal denervation reduc-

es left ventricular mass in patients with resistant hypertension-results from a multicenter

CMR-study. Journal of Cardiovascular Magnetic Resonance 2013b;Conference

(var.pagings):85.

Pokushalov E, Romanov A, Corbucci G, Artyomenko S, Baranova V, Turov A, Shirokova N,

Karaskov A, Mittal S, Steinberg JS. A randomized comparison of pulmonary vein isolation with

versus without concomitant renal artery denervation in patients with refractory symptomatic

atrial fibrillation and resistant hypertension. J Am Coll Cardiol 2012;60(13):1163-70.

Importance and transferability

How important is this piece of information for decision making?

Critical

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Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

D0006: How does renal denervation affect progression of treatment-resistant arterial

hypertension?

BP

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information: Davis 2013 (SR) for both three and six months’ follow-up and Ahmed

2012b (RCT) for three months follow-up

Basic documentation

Domain search

Other:

Critical appraisal criteria: for the SR, we used the NOKC check-list for systematic reviews and

Cochrane risk of bias (RoB) checklist for RCTs and non-RCTs; for the study by Ahmed et al.,

results were reported narratively, as we lacked information on the type of catheter used and

variability of data (SE, SD or CI), and the type of test used to generate p-values.

Method for synthesis: RevMan and GRADE. Davis et al. performed meta-analyses of controlled

studies (two RCTs and one non-RCT, i.e. (prospective controlled trial), and studies having

used different types of catheters (one RCT used the Navistar ThermoCool®, while one RCT

and one non-RCT used the Symplicity® system). We therefore chose to re-perform the meta-

analyses so that we also could show the separate estimates for each of the catheter types.

Davis et al. stated that once full articles were retrieved, studies were further excluded if there

was an overlap in patients with another study within the same analysis (in which case the

largest sample size of the two studies was selected). In this way, overlaps of patients were

avoided in the meta-analyses.

Result

Change in BP after 3 months

Change in systolic BP (3 months)

Three controlled studies having assessed change in systolic BP at three months (two RCTs

and one non-RCT) using different types of catheters (one RCT used the Navistar® Thermo-

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Cool®, while one RCT and one non-RCT used the Symplicity® system) were pooled

(Pokushalov 2012; Symplicity HTN-2 Investigators, Esler 2010; Krum 2009). They included

171 patients in total (101 in the intervention group and 70 in the control group). The total

estimate showed a significant decrease in systolic BP (Figure EFF1) with a mean difference of

20.8 mm Hg with a 95 % CI (15.2 – 26.4 mm Hg), thus in favor of renal denervation. The qual-

ity of the evidence was low (Table EFF3).

We re-analyzed the data, and grouped studies according to catheter type. Pooling the two

studies including totally 144 patients (88 in the intervention group and 56 in the control

group) that used the Symplicity® system (Figure EFF1) resulted in a decrease of

20.6 mm Hg systolic BP with 95 % CI (12.1 – 20.1 mm Hg), which was significant. Here, the

quality of the evidence was moderate (Table EFF3).

As shown in Figure EFF1, the study that used the Navistar® ThermoCool® system included

27 patients (13 in the intervention group and 14 in the control group) showed a mean differ-

ence of 21 mm Hg with 95 % CI (13.6 – 28.4 mm Hg), a decrease which also was significant.

However in this case, the quality of the evidence was very low (Table EFF3).

Figure EFF1: Forest plots of change in systolic BP after 3 months

Change in diastolic BP (3 months)

As for systolic BP, the three controlled studies having assessed change in diastolic BP at three

months (two RCTs and one non-RCT) using different types of catheters (one RCT used the

Navistar® ThermoCool®, while one RCT and one non-RCT used the Symplicity® system) were

pooled (Pokushalov 2012; Symplicity HTN-2 Investigators, Esler 2010; Krum 2009). Likewise,

they included 171 patients in total (101 in the intervention group and 70 in the control

group). The total estimate showed a significant decrease in diastolic BP (Figure EFF2) with a

mean difference of 7.6 mm Hg with 95 % CI (4.2 – 11.0 mm Hg). The quality of the evidence

was low (Table EFF3).

Study or Subgroup

4.1.1 Symplicity

Esler 2010 (HTN-2)

Krum 2009

Subtotal (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 0.11, df = 1 (P = 0.74); I² = 0%

Test for overall effect: Z = 4.74 (P < 0.00001)

4.1.2 Navistar

Pokushalov 2012

Subtotal (95% CI)

Heterogeneity: Not applicable

Test for overall effect: Z = 5.56 (P < 0.00001)

Total (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 0.11, df = 2 (P = 0.95); I² = 0%

Test for overall effect: Z = 7.31 (P < 0.00001)

Test for subgroup differences: Chi² = 0.01, df = 1 (P = 0.94), I² = 0%

Mean

-24

-21

-27

SD

25

22

9.8

Total

49

39

88

13

13

101

Mean

-4

3

-6

SD

21.9

24

9.8

Total

51

5

56

14

14

70

Weight

36.6%

6.4%

43.0%

57.0%

57.0%

100.0%

IV, Random, 95% CI

-20.00 [-29.23, -10.77]

-24.00 [-46.14, -1.86]

-20.59 [-29.11, -12.08]

-21.00 [-28.40, -13.60]

-21.00 [-28.40, -13.60]

-20.82 [-26.41, -15.24]

Renal denervation Control Mean Difference Mean Difference

IV, Random, 95% CI

-100 -50 0 50 100

Favours renal denervation Favours control

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Figure EFF2. Forest plots of change in diastolic BP after 3 months

We re-analysed the data, and grouped studies according to catheter type, as for systolic BP at

three months. Pooling the two studies including totally 144 patients (88 in the intervention

group and 56 in the control group) that used the Symplicity® system (Figure EFF2) resulted in

a mean difference of 8.0 mm Hg with 95 % CI (1.8 – 14.2 mm Hg), a decrease in diastolic BP

which also was significant. The quality of the evidence was moderate (Table EFF3).

As shown in Figure EFF2, and as for systolic BP, the study that used the Navistar® Thermo-

Cool® system included 27 patients (13 in the intervention group and 14 in the control group)

showed a mean difference of 8.0 mm Hg with 95 % CI (2.8 – 13.2 mm Hg), a decrease which

was significant too. The quality of the evidence was very low (Table EFF3).

Davis et al. showed separately mean differences in systolic BP at three months after renal

denervation in which they included patients from the intervention group of RCTs, non-RCTs

and observational studies for the different types of renal denervation systems. As shown in

Table EFF2, 6 studies using the Symplicity® system were pooled, which resulted in a signifi-

cant decrease in systolic BP. However, except for one trial, the studies lacked control group.

Four other studies were presented which also assessed systolic BP at three months using

Celcius® ThermoCool®, Navistar® ThermoCool®, MarinR® and PARADISETM

systems respec-

tively (Ahmed 2012a; Pokushalov 2012; Prochnau 2012a; Mabin 2012). Each study indicated

decreases in systolic BP, which also were significant. As these trials are mostly without a con-

trol group, and we have results from controlled trials on this outcome, we have not per-

formed GRADE evaluations for

Table EFF2. Difference in systolic BP (3 months)

Catheter type Studies

included

Number of patients

(pre- and post treatment)

Estimate

(mean difference in mm Hg)

Symplicity® 6 379 – 341 -21,18 (-25,77 to -16,59)

Celcius® ThermoCool® 1 10 – 10 -22 (-28 ,80 to -15,20)

Navistar® ThermoCool® 1 13 – 13 -27,00 (-32,33 to -21,67)

Marinr® 1 30 – 30 -25,50 (-32,65 to -18,35)

PARADISETM

1 10 – 8 -36,00 (-49,86 to -22,14)

The RCT by Ahmed and colleagues (Ahmed 2012b) included 40 patients with drug-resistant

hypertension (19 in the intervention group and 21 in the control group). They reported hav-

ing used an off-the shelf saline-irrigated radiofrequency ablation catheter typically employed

for cardiac tissue ablation, but do not mention from whom this catheter was purchased (Ah-

med 2012b). After three months, systolic BP was decreased by 11 mm Hg (p-value 0.006)

while diastolic BP was decreased by 7 mm Hg, however lack of key information to date, as

mentioned in the method section above, prevents us for assessing the quality of the evidence

thus drawing any conclusions.

Study or Subgroup

4.2.1 Symplicity

Esler 2010 (HTN-2)

Krum 2009

Subtotal (95% CI)

Heterogeneity: Tau² = 7.52; Chi² = 1.44, df = 1 (P = 0.23); I² = 31%

Test for overall effect: Z = 2.53 (P = 0.01)

4.2.2 Navistar

Pokushalov 2012

Subtotal (95% CI)

Heterogeneity: Not applicable

Test for overall effect: Z = 3.01 (P = 0.003)

Total (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 1.48, df = 2 (P = 0.48); I² = 0%

Test for overall effect: Z = 4.39 (P < 0.0001)

Test for subgroup differences: Chi² = 0.00, df = 1 (P = 1.00), I² = 0%

Mean

-8

-10

-12

SD

14.3

12.7

5.88

Total

49

39

88

13

13

101

Mean

-2

3

-4

SD

10.9

10.8

7.84

Total

51

5

56

14

14

70

Weight

46.3%

11.0%

57.3%

42.7%

42.7%

100.0%

IV, Random, 95% CI

-6.00 [-11.00, -1.00]

-13.00 [-23.27, -2.73]

-8.00 [-14.20, -1.80]

-8.00 [-13.20, -2.80]

-8.00 [-13.20, -2.80]

-7.62 [-11.02, -4.22]

Renal denervation Control Mean Difference Mean Difference

IV, Random, 95% CI

-100 -50 0 50 100

Favours renal denervation Favours control

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Change in BP after 6 months

Change in systolic BP (6 months)

As for systolic BP measured at three months, three controlled studies had assessed change in

systolic BP at six months (two RCTs and one non-RCT) using different types of catheters (one

RCT used the Navistar® ThermoCool®, while one RCT and one non-RCT used the Symplicity®

system) were pooled (Pokushalov 2012; Symplicity HTN-2 Investigators, Esler 2010; Krum

2009). They included 158 patients (88 in the intervention group and 70 in the control group).

The overall estimate for renal denervation showed a significant decrease in systolic BP (Figure

EFF3) with a mean difference of 29.8 mm Hg with a 95% CI (20.6 – 37.2 mm Hg). The quality

of the evidence was low (Table EFF3).

We re-analyzed the data, and grouped studies according to catheter type. Pooling the two

studies including totally 131 patients (75 in the intervention group and 56 in the control

group) that used the Symplicity® system (Figure EFF3) resulted in a mean difference of 33.6

mm Hg with 95 % CI (25.9 – 41.3 mm Hg), which was significant. The quality of the evidence

was moderate (Table EFF3).

As shown in Figure EFF3, the study that used the Navistar® ThermoCool® system included 27

patients (13 in the intervention group and 14 in the control group) showed a mean difference

of 23 mm Hg with 95 % CI (16.8 – 29.2 mm Hg), which also was significant. The quality of the

evidence was very low (Table EFF3).

Figure EFF3. Forest plots of change in systolic BP after 6 months

Change in diastolic BP (6 months)

As for systolic BP, the three controlled studies having assessed change in diastolic BP at six

months (two RCTs and one non-RCT) using different types of catheters (one RCT used the

Navistar® ThermoCool®, while one RCT and one non-RCT used the Symplicity® system) were

pooled (Pokushalov 2012; Symplicity HTN-2 Investigators, Esler 2010; Krum 2009). Likewise,

they included 158 patients (88 in the intervention group and 70 in the control group). The

total estimate showed a significant decrease in diastolic BP (Figure EFF4) with a mean differ-

ence of 11.0 mm Hg with 95 % CI (5.7 – 16.4 mm Hg). The quality of this evidence was low

(Table EFF3).

We re-analyzed the data, and grouped studies according to catheter type, as for systolic BP at

three months. Pooling the two studies including 131 patients (75 in the intervention group

Study or Subgroup

4.3.1 Symplicity

Esler 2010 (HTN-2) (1)

Krum 2009 (2)

Subtotal (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 0.09, df = 1 (P = 0.76); I² = 0%

Test for overall effect: Z = 8.53 (P < 0.00001)

4.3.2 Navistar

Pokushalov 2012 (3)

Subtotal (95% CI)

Heterogeneity: Not applicable

Test for overall effect: Z = 7.29 (P < 0.00001)

Total (95% CI)

Heterogeneity: Tau² = 28.93; Chi² = 4.50, df = 2 (P = 0.11); I² = 56%

Test for overall effect: Z = 6.83 (P < 0.00001)

Test for subgroup differences: Chi² = 4.41, df = 1 (P = 0.04), I² = 77.3%

Mean

-32

-22

-28

SD

23

26

9.8

Total

49

26

75

13

13

88

Mean

1

14

-5

SD

21

16

6

Total

51

5

56

14

14

70

Weight

37.0%

16.9%

53.9%

46.1%

46.1%

100.0%

IV, Random, 95% CI

-33.00 [-41.64, -24.36]

-36.00 [-53.22, -18.78]

-33.60 [-41.33, -25.88]

-23.00 [-29.19, -16.81]

-23.00 [-29.19, -16.81]

-28.90 [-37.20, -20.60]

Renal denervation Control Mean Difference

(1) Baseline RD 178+/-18, Control 178+/-17

(2) Baseline RD 177+/-20, Control 173+/-8

(3) Baseline RD 181+/-7, Control 178+/-8

Mean Difference

IV, Random, 95% CI

-100 -50 0 50 100

Favours renal denervation Favours control

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and 56 in the control group) that used the Symplicity® system (Figure EFF4) resulted in a

mean difference of 13.8 mm Hg with 95 % CI (7.3 – 20.3 mm Hg), which also was significant.

The quality of this evidence was moderate (Table EFF3).

As shown in Figure EFF4, as for systolic BP, the study that used the Navistar® ThermoCool®

system included 27 patients (13 in the intervention group and 14 in the control group) and

showed a mean difference of 7.0 mm Hg with 95 % CI (2.5 – 11.5 mm Hg), which was signifi-

cant too. The quality of the evidence was very low (Table EFF3).

Figure EFF4. Forest plots of change in systolic BP after 6 months

Table EFF3. GRADE profiles for BP

Quality assessment No of patients Effect

Quality Importance

No of studies

Design Risk of bias

Inconsistency Indirectness Imprecision Other consider-ations

Renal denervation

Control Relative (95% CI)

Absolute

Change in systolic BP at 3 months (measured with: Office-based (mm Hg); better indicated by lower values)

3 2 RCTs 1 non-RCT

no serious risk of bias

1

no serious inconsistency

serious2,3

serious4 none 101 70 - MD 20.82 lower

(26.41 to 15.24 lower)

LOW

CRITICAL

Change in systolic BP at 3 months - Symplicity (measured with: Office-based (mm Hg); better indicated by lower values)

2 1 RCTs 1 non-RCT

no serious risk of bias

1

no serious inconsistency

no serious indirectness

serious4 none 88 56 - MD 20.59 lower

(29.11 to 12.08 lower)

MODERATE

CRITICAL

Change in systolic BP at 3 months - Navistar (measured with: Office based (mm Hg); better indicated by lower values)

1 RCT no serious risk of bias

no serious inconsistency

serious2,5

very serious4 none 13 14 - MD 21 lower

(28.4 to 13.6 lower)

VERY LOW

CRITICAL

Change in diastolic BP at 3 months (measured with: Office based (mm Hg); better indicated by lower values)

3 2 RCTs 1 non-RCT

no serious risk of bias

1

no serious inconsistency

serious2,3

serious4 none 101 70 - MD 7.62 lower

(11.02 to 4.22 lower)

LOW

CRITICAL

Change in diastolic BP at 3 months - Symplicity (measured with: Office based (mm Hg); better indicated by lower values)

2 1 RCTs 1 non-RCT

no serious risk of bias

1

no serious inconsistency

no serious indirectness

serious4 none 88 56 - MD 8 lower

(14.2 to 1.8 lower)

MODERATE

CRITICAL

Change in diastolic BP at 3 months - Navistar (measured with: Office based (mm Hg); better indicated by lower values)

1 RCT no serious risk of bias

no serious inconsistency

serious2 very seri-

ous4,5

none 13 14 - MD 8 lower

(13.2 to 2.8 lower)

VERY LOW

CRITICAL

Change in systolic BP at 6 months (measured with: Office based (mm Hg); better indicated by lower values)

3 2 RCTs 1 non-RCT

no serious risk of bias

1

no serious inconsistency

serious2,3

serious4 none 88 70 - MD 29.80 lower

(37.2 to 20.6 lower)

LOW

CRITICAL

Change in systolic BP at 6 months - Symplicity (measured with: Office based (mm Hg); better indicated by lower values)

2 1 RCTs 1 non-RCT

no serious risk of bias

1

no serious inconsistency

no serious indirectness

serious4 none 75 56 - MD 33.6 lower

(41.33 to 25.88 lower)

MODERATE

CRITICAL

Change in systolic BP at 6 months - Navistar (follow-up 6 months; measured with: Office based (mm Hg); better indicated by lower values)

1 RCT no serious risk of bias

no serious inconsistency

serious2 very seri-

ous4,5

none 13 14 - MD 23 lower

(29.2 to 16.8 VERY LOW

CRITICAL

Study or Subgroup

4.4.1 Symplicity

Esler 2010 (HTN-2) (1)

Krum 2009 (2)

Subtotal (95% CI)

Heterogeneity: Tau² = 9.63; Chi² = 1.43, df = 1 (P = 0.23); I² = 30%

Test for overall effect: Z = 4.15 (P < 0.0001)

4.4.2 Navistar

Pokushalov 2012 (3)

Subtotal (95% CI)

Heterogeneity: Not applicable

Test for overall effect: Z = 3.03 (P = 0.002)

Total (95% CI)

Heterogeneity: Tau² = 12.61; Chi² = 5.03, df = 2 (P = 0.08); I² = 60%

Test for overall effect: Z = 4.03 (P < 0.0001)

Test for subgroup differences: Chi² = 2.80, df = 1 (P = 0.09), I² = 64.3%

Mean

-12

-11

-10

SD

11

13

6

Total

49

26

75

13

13

88

Mean

0

9

-3

SD

10

13

6

Total

51

5

56

14

14

70

Weight

44.0%

14.2%

58.2%

41.8%

41.8%

100.0%

IV, Random, 95% CI

-12.00 [-16.13, -7.87]

-20.00 [-32.44, -7.56]

-13.76 [-20.25, -7.27]

-7.00 [-11.53, -2.47]

-7.00 [-11.53, -2.47]

-11.04 [-16.41, -5.68]

Renal denervation Control Mean Difference

(1) Baseline RD: 96+/-16, Control:97+/-16

(2) Baseline RD 101+/-15, Control 98+/-9

(3) Baseline RD 97+/-6, Control 96+/-4

Mean Difference

IV, Random, 95% CI

-100 -50 0 50 100

Favours renal denervation Favours control

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lower)

Change in diastolic BP at 6 months (follow-up 6 months; measured with: Office based (mm Hg); better indicated by lower values)

3 2 RCTs 1 non-RCT

no serious risk of bias

1

no serious inconsistency

serious2,3

serious4 none 88 70 - MD 11.04 lower

(16.41 to 5.68 lower)

LOW

CRITICAL

Change in diastolic BP at 6 months - Symplicity (measured with: Office based; better indicated by lower values)

2 1 RCTs 1 non-RCT

no serious risk of bias

1

no serious inconsistency

no serious indirectness

serious4 none 75 56 - MD 13.76 lower

(20.25 to 7.27 lower)

MODERATE

CRITICAL

Change in diastolic BP at 6 months - Navistar (measured with: Office based (mm Hg); better indicated by lower values)

1 RCT no serious risk of bias

no serious inconsistency

serious2 very seri-

ous4,5

none 13 14 - MD 7 lower

(11.53 to 2.47 lower)

VERY LOW

CRITICAL

1 Mix of randomised and non-randomised CT (combined as in the SR).

2 Tested pulmonary vein isolation +/- renal denervation. Participants had atrial fibrillation in addition to treatment-resistant hypertension.

3 Combination of different catheter types. Uncertain transferability.

4 Few participants (GRADE give suggested recommendation for imprecision: total population size is less than 400 (a threshold rule-of-thumb value; using the usual α and

β, and an effect size of 0.2 SD, representing a small effect). 5 Only one study, unknown reproducibility.

Discussion

All three controlled studies identified by the SR included in this rapid assessment showed a

statistically significant decrease in systolic and diastolic BP both after three (171 patients)

and six months (158 patients) of follow-up, thus favored renal denervation. The quality of the

evidence was however variable when assessed using GRADE, ranging from very low (one

study including 27 patients that used the Navistar® ThermoCool® system) to moderate (two

studies including 144 patients after three months’ follow-up and 131 patients at six months’

follow-up using the Symplicity® system). We therefore conclude that renal denervation using

the Symplicity® system seems to decrease BP, while there is uncertainty about effect on BP

using the Navistar® ThermoCool® system.

In this rapid assessment we identified 26 ongoing studies in the ICTRP database, most focus

on BP control (see Appendix 1).

Supplementary documentation received from the other manufacturers (Boston Scientific, St

Jude and Covidien, Medtronic) indicate that these companies plan their first, or additional

RCT in the next year or two.

References

Ahmed H, Neuzil P, Skoda J, Petru J, Sediva L, Schejbalova M, Reddy VY. Renal sympathetic

denervation using an irrigated radiofrequency ablation catheter for the management of drug-

resistant hypertension. JACC Cardiovasc Interv 2012a;5(7):758-65.

Ahmed H, Neuzil P, Schejbalova M, Bejr M, Kralovec S, Reddy VY. Renal sympathetic denerva-

tion for the management of chronic hypertension (Relief): 40 patient analysis. Circulation

2012b;Conference (var.pagings)

Davis MI, Filion KB, Zhang D, Eisenberg MJ, Afilalo J, Schiffrin EL, Joyal D. Effectiveness of re-

nal denervation therapy for resistant hypertension: a systematic review and meta-analysis. J

Am Coll Cardiol 2013;62(3):231-241.

Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sie-

vert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for

resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet

2009;373(9671):1275-81.

Mabin T, Sapoval M, Cabane V, Stemmett J, Iyer M. First experience with endovascular ultra-

sound renal denervation for the treatment of resistant hypertension. EuroIntervention

2012;8(1):57-61

Pokushalov E, Romanov A, Corbucci G, Artyomenko S, Baranova V, Turov A, Shirokova N,

Karaskov A, Mittal S, Steinberg JS. A randomized comparison of pulmonary vein isolation with

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versus without concomitant renal artery denervation in patients with refractory symptomatic

atrial fibrillation and resistant hypertension. J Am Coll Cardiol 2012;60(13):1163-70.

Prochnau D, Figulla HR, Surber R. Efficacy of renal denervation with a standard EP catheter in

the 24-h ambulatory blood pressure monitoring-long-term follow-up. Int J Cardiol

2012a;157(3):447-8.

Symplicity HTN-2 Investigators, Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE,

Böhm M. Renal sympathetic denervation in patients with treatment-resistant hypertension

(The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376(9756):1903-09.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

D0011: What is the effect of renal denervation on patients’ body functions?

Kidney function

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information: Gosain 2013 (SR)

Basic documentation

Domain search

Other:

Critical appraisal criteria: NOKC check-list for systematic reviews

Method of synthesis: GRADE

Result

Change in eGFR (estimated Glomerular Filtration Rate)

The SR by Gosain et al. (Gosain 2013) identified one RCT including 100 patients (49 in the

intervention group and 51 in the control group) which assessed change in renal function in

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terms of change in eGFR (estimated Glomerular Filtration Rate) after six months of follow up

using the Symplicity® system (Symplicity HTN-2 Investigators, Esler 2010). The mean differ-

ence between the two groups was 0.7 mL/min/1.73m2

(baseline levels retrieved from Esler et

al. were 77+/-17 mL/min/1.73m2

in the renal denervation group and 86+/-20

mL/min/1.73m2

in the control group) and not significant. The quality of this evidence was

low (Table EFF4).

Change in serum creatinine levels

The same RCT with 100 patients (also with 49 in the intervention group and 51 in the control

group) assessed change in renal function in terms of change in serum creatinine levels after

six months of follow up using the Symplicity® system (Symplicity HTN-2 Investigators, Esler

2010). The mean difference between the two groups was 1.3 µmol/L (baseline levels re-

trieved from Esler et al. were 91+/-25 µmol/L in the renal denervation group and 78+/-18

µmol/L in the control group) and not significant. The quality of this evidence was low (Table

EFF4).

Table EFF4. GRADE profiles for kidney function

Quality assessment No of patients Effect

Quality Importance

No of studies

Design Risk of bias

Inconsistency Indirectness Imprecision Other consider-ations

Renal denervation

Control Relative (95% CI)

Absolute

Change in eGFR at 6 months - RCT (measured with: lab analysis (estimated glomerular filtration rate in mL/min/1.73m2); better indicated by lower values)

1 RCT no serious risk of bias

no serious inconsistency

no serious indirectness

very seri-ous

1,2

none 49 51 - MD 0.7 lower (5.21 lower to 3.81 higher)

LOW

IMPORTANT

Change in creatinine at 6 months - RCT (measured with: lab analysis (creatinine in µmol/L); better indicated by lower values)

1 RCT no serious risk of bias

no serious inconsistency

no serious indirectness

very seri-ous

1,2

none 49 51 - MD 1.3 higher (4.38 lower to 6.98 higher)

LOW

IMPORTANT

1 Few participants (GRADE give suggested recommendation for imprecision : total population size is less than 400 (a threshold rule-of-thumb value; using the usual α and

β, and an effect size of 0.2 SD, representing a small effect). 2 Only one study, unknown reproducibility

Discussion

According to one RCT with 100 patients identified by the included SR, there was no change in

kidney function assessed by measuring eGFR and creatinine levels following renal denerva-

tion at six months’ follow-up, however no definite conclusion can be drawn as the quality of

the evidence is low.

References

Symplicity HTN-2 Investigators, Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE,

Böhm M. Renal sympathetic denervation in patients with treatment-resistant hypertension

(The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376(9756):1903-

1909.

Gosain P, Garimella PS, Hart PD, Agarwal R. Renal Sympathetic Denervation for Treatment of

Resistant Hypertension: A Systematic Review. J Clin Hypertens 2013;15(1):75-84.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

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How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

D0016: How does the use of renal denervation affect activities of daily living?

Exercise

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information: Ukena 2011 (RCT)

Basic documentation

Domain search

Other:

Critical appraisal criteria: Cochrane risk of bias checklist for RCTs

Method of synthesis: GRADE

Result

Change in maximum work rate

One RCT including 46 patients (37 in the intervention group and 9 in the control group) as-

sessed change in maximum work rate after three months’ of follow-up after renal denervation

using the Symplicity® system (Ukena 2011). The mean difference between the two groups

was 3.0 Watts on reclining ergometer (baseline levels were 123+/-36 Watts in the renal de-

nervation group and 130+/-26 Watts in the control group) and not significant. The quality of

this evidence was very low (Table EFF5).

Change in peak oxygen uptake

The same RCT assessed change in peak oxygen uptake (VO2

peak) three months’ after renal

denervation using the Symplicity® system (Ukena 2011). The mean difference between the

two groups was 1.0 ml/min/kg (baseline levels were 19+/-4 ml/min/kg in the renal denerva-

tion group and 20+/-4 ml/min/kg in the control group) and not significant. The quality of

this evidence was very low (Table EFF5).

Table EFF5. GRADE profiles for activities of daily living (exercise)

Quality assessment No of patients Effect

Quality Importance

No of studies

Design Risk of bias

Inconsistency Indirectness Imprecision Other consider-ations

Activity of daily living: exercise

Control Relative (95% CI)

Absolute

Change in max work rate at 3 months (follow-up 3 months; measured with: Watts on reclining ergometer; Better indicated by lower values)

1 RCT serious risk of

no serious inconsistency

no serious indirectness

2

very seri-ous

3,4

none 37 9 - MD 3 higher (7.66 lower to 13.66

VERY

IMPORTANT

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bias1 higher) LOW

Change in peak oxygen uptake at 3 months (follow-up 3 months; measured with: VO2 peak ml/min/kg; Better indicated by higher values)

1 RCT serious risk of bias

1

no serious inconsistency

no serious indirectness

2

very seri-ous

3,4

none 37 9 - MD 1.00 lower (2.46 lower to 0.46 higher)

VERY LOW

IMPORTANT

1 Unclear how randomization and allocation was performed.

2 Unclear how well this test represent the patients' ability to manage activity of daily living.

3 Only one study, unknown reproducibility

4 Few participants (GRADE give suggested recommendation for imprecision : total population size is less than 400 (a threshold rule-of-thumb value; using the usual α and

β, and an effect size of 0.2 SD, representing a small effect).

Discussion

According to one RCT (including 46 patients) identified in this rapid assessment, there was

no change in activities of daily living in terms of exercise assessed with measurements of

maximum work rates and peak oxygen uptake following renal denervation at three months’

follow-up, however no definite conclusion could be drawn as the quality of the evidence was

low.

References

Ukena C, Mahfoud F, Kindermann I, Barth C, Lenski M, Kindermann M, et al. Cardiorespiratory

response to exercise after renal sympathetic denervation in patients with resistant hyperten-

sion. J Am Coll Cardiol 2011;58(11):1176-82.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

D0012: What is the effect of renal denervation on generic health-related quality of life?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information: No SR or RCT or non-RCT (i.e. prospective controlled trial) found

Basic documentation

Domain search

Other:

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Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

None of the identified studies in this rapid assessment have addressed generic health-related

quality of life.

Discussion

Since none of the identified studies in this rapid assessment have addressed generic health-

related quality of life, no conclusion can be drawn. None of the ongoing studies identified in

this rapid assessment are assessing this research question.

References

-

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

D0013: What is the effect of renal denervation on disease-specific quality of life?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information: No SR or RCT or non-RCT (i.e. prospective controlled trial) found

Basic documentation

Domain search

Other:

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Critical appraisal criteria: not applicable

Method of synthesis: not applicable

Result

None of the identified studies in this rapid assessment have addressed disease-specific quali-

ty of life.

Discussion

Since none of the identified studies in this rapid assessment have addressed disease-specific

quality of life, no conclusion can be drawn. None of the ongoing studies identified in this

rapid assessment are assessing this research question.

References

-

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

D0017: Were patients overall satisfied with renal denervation?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information: No SR or RCT or non-RCT (i.e. prospective controlled trial) found

Basic documentation

Domain search

Other:

Critical appraisal criteria: not applicable

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Method of synthesis: not applicable

Result

None of the identified studies in this rapid assessment have addressed patient satisfaction.

Discussion

Since none of the identified studies in this rapid assessment have addressed patient satisfac-

tion, no conclusion can be drawn. None of the ongoing studies identified in this rapid as-

sessment are assessing this research question.

References

-

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

D0018: Would the patient be willing to undergo renal denervation?

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information: No SR or RCT or non-RCT (i.e. prospective controlled trial) found

Basic documentation

Domain search

Other:

Critical appraisal criteria: not applicable

Method of synthesis: not applicable

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Result

None of the identified studies in this rapid assessment have addressed patients’ willingness

to undergo renal denervation.

Discussion

Since none of the identified studies in this rapid assessment have addressed patients’ will-

ingness to undergo renal denervation, no conclusion can be drawn. None of the ongoing

studies identified in this rapid assessment are assessing this research question.

References

-

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

D0023: How does renal denervation modify the need for other technologies and use of

resources?

Decrease in number of medications

Methods

See general description of methods (Appendix 1)

Other, please specify:

Source of information: Gosain 2013 (SR)

Basic documentation

Domain search

Other:

Critical appraisal criteria: NOKC check-list for systematic reviews

Method of synthesis: narrative (GRADE not applicable)

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Result

Decrease in number of medications

Gosain and colleagues narratively summarised the change in number of medications in their

included studies (Gosain 2013). They stated that average number of antihypertensive medica-

tions used in most studies were five, and reported change in number of antihypertensive

medications after renal denervation in nine studies. Table EFF6 below, tabulates the infor-

mation Gosain and colleagues present in text. It shows number of studies and number of

patients included in these studies with the corresponding recorded changes in medications

and number of patients related to the change in question.

Table EFF6. Change in number of antihypertensive medications

Studies (total number of patients) Change In how many/which patients?

3 (236) 10 - 20 % decrease 52 patients

10 – 25 % increase 25 patients

1 (5) Decrease (? %) 4 patients

3 (129 ) 15 - 25 % decrease Not specified

2 (60) No change Not specified

In three studies with totally 236 patients, 52 patients noted the 10-20% reduction in the

number of antihypertensive medications used, while 25 patients required 10 to 25 % (in-

crease in the number of medications. One study with 5 patients reported reduction in antihy-

pertensive medications in 4 patients. Further, three studies including 129 patients in total

reported a decrease in medications of 15 to 25 % in renal denervation group. Finally, the re-

maining studies with a total of 60 patients reported no change in number of medications.

Discussion

Although data from nine studies including 430 patients in total may suggest a decrease in

number of anti-hypertensive medications following renal denervation, no conclusion can be

drawn.

References

Gosain P, Garimella PS, Hart PD, Agarwal R. Renal Sympathetic Denervation for Treatment of

Resistant Hypertension: A Systematic Review. J Clin Hypertens 2013;15(1):75-84.

Importance and transferability

How important is this piece of information for decision making?

Critical

Important

Optional

How transferable is this piece of information, i.e. can it be used in national decisions as such?

Completely

Partly

Not

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APPENDIX 3: CHECKLIST FOR POTENTIAL ETHICAL, ORGANISATIONAL,

SOCIAL AND LEGAL ASPECTS

Checklist for potential ethical, organisational, social and legal aspects

1. Ethical

1.1. Does the introduction of renal denervation and its potential use/nonuse

instead of the defined, existing comparator(s) give rise to any new ethical

issues (equal access to the treatment, resource allocation/shortage etc.)?

Yes

1.2. Does comparing renal denervation to the defined, existing comparators

point to any differences which may be ethically relevant?

No

2. Organisational

2.1. Does the introduction of renal denervation and its potential use/nonuse

instead of the defined, existing comparators require organisational

changes in terms of training in procedure, need for facilities, equipment

and resources?

Yes

2.2. Does comparing renal denervation to the defined, existing comparators

point to any differences which may be organisationally relevant (e.g. shift

from primary to secondary care, transportation, etc.)?

Yes

3. Social

3.1. Does the introduction of renal denervation and its potential use/nonuse

instead of the defined, existing comparator(s) give rise to any new social

issues?

No

3.2. Does comparing renal denervation to the defined, existing comparators

point to any differences which may be socially relevant?

No

4. Legal

4.1. Does the introduction of renal denervation and its potential use/nonuse

instead of the defined, existing comparator(s) give rise to any legal is-

sues?

No

4.2. Does comparing renal denervation to the defined, existing comparators

point to any differences which may be legally relevant?

No